Next Article in Journal
Benefits of Conversion Surgery after Multimodal Treatment for Unresectable Pancreatic Ductal Adenocarcinoma
Next Article in Special Issue
The Long and Short of It: The Emerging Roles of Non-Coding RNA in Small Extracellular Vesicles
Previous Article in Journal
Retrospective Multicentric Study on Non-Optic CNS Tumors in Children and Adolescents with Neurofibromatosis Type 1
Previous Article in Special Issue
The Good, the Bad, the Question–H19 in Hepatocellular Carcinoma
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 12
Issue 6
10.3390/cancers12061424
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Long Noncoding RNAs Involved in the Endocrine Therapy Resistance of Breast Cancer

by
Toshihiko Takeiwa
1,
Kazuhiro Ikeda
1,
Yuichi Mitobe
1,
Kuniko Horie-Inoue
1 and
Satoshi Inoue
1,2,*
1
Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan
2
Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1424; https://doi.org/10.3390/cancers12061424
Submission received: 31 March 2020 / Revised: 25 May 2020 / Accepted: 27 May 2020 / Published: 31 May 2020
(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)
Browse Figures
Versions Notes

Abstract

:
Long noncoding RNAs (lncRNAs) are defined as RNAs longer than 200 nucleotides that do not encode proteins. Recent studies have demonstrated that numerous lncRNAs are expressed in humans and play key roles in the development of various types of cancers. Intriguingly, some lncRNAs have been demonstrated to be involved in endocrine therapy resistance for breast cancer through their own mechanisms, suggesting that lncRNAs could be promising new biomarkers and therapeutic targets of breast cancer. Here, we summarize the functions and mechanisms of lncRNAs related to the endocrine therapy resistance of breast cancer.

1. Introduction

For women worldwide, breast cancer is the most common cancer, and one in eight to ten women will develop breast cancer during their lifetime [1,2]. Although the endocrine therapies that target sex hormone receptor signaling pathways are effective treatment for breast cancer, therapy resistance and cancer recurrence remain important issues, and novel therapeutic strategies are required. Recent transcriptome analyses have revealed that a large number of long noncoding RNAs (lncRNAs), which are RNAs that are longer than 200 nucleotides in length and do not encode proteins, are expressed in humans [3,4,5]. LncRNAs play key roles in various biological process and diseases, including cancers [6,7,8,9,10]. In breast cancer, some lncRNAs exert oncogenic or tumor-suppressive functions to control breast cancer pathophysiology, such as invasion and metastasis, and drug resistance; these findings are summarized in a recent review article [11]. In terms of endocrine therapy, selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders or downregulators (SERDs), and aromatase inhibitors, are mainly used as drugs to suppress estrogen signaling. For an experimental model of aromatase inhibitor-resistant breast cancer, cells that can obtain the ability to grow under long-term estrogen deprivation (LTED) conditions are preferentially used. Here, we extensively focus on endocrine therapy resistance-associated lncRNAs in breast cancer by including these drugs and experimental models, and describe the recent findings on their functions and mechanisms.

2. Breast Cancer

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in women worldwide [1,2]. According to the GLOBOCAN 2018 database of the International Agency for Research on Cancer, which estimates the incidence and mortality of several cancers, the number of new cases of breast cancer in 2018 was estimated at 2,088,849, and those of deaths due to breast cancer are estimated as 1,276,106 [2]. Breast cancer is classified into at least four subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)/erythroblastic oncogene B 2 (ErbB2)-enriched, and basal-like) based on gene expression patterns [1,12,13]. The luminal subtypes are sex hormone receptor-positive [estrogen receptor (ER) or progesterone receptor (PR)-positive] and HER2-negative, and the HER2-enriched subtype is HER2-positive, while the basal-like subtype is ER-, PR-, and HER2-negative. The majority of breast cancers belong to luminal subtypes and are primarily sensitive to estrogen and progesterone [14,15,16]. The receptors of these hormones, ER and PR, respectively, function as ligand-dependent transcription factors. After binding to their ligands, these hormone receptors dimerize and associate with DNA through their DNA-binding domains. These hormone receptors form complexes with other transcription factors and co-regulators, such as the steroid receptor coactivator (SRC)/p160 family proteins and CREB-binding protein (CBP)/p300, and control the transcription of their target genes [17,18,19]. As sex hormone signaling pathways are essential for breast cancer pathophysiology, therapies targeting the hormones and their receptors, or endocrine therapies, remain the standard treatment for breast cancer [20,21]. For instance, drugs that suppress estrogen signaling or estrogen production are used for endocrine therapies. To suppress estrogen-mediated ER activation, drugs such as SERMs and SERDs are used. Although both SERMs and SERDs compete with estrogen, their mechanisms for the regulation of ER signaling are different. SERMs affect the interaction between the ER and co-factors, leading to changes in ER-targeted gene expression. Thus, SERMs, such as tamoxifen and raloxifene, act as ER antagonists in breast cancer and are used for breast cancer therapy or prevention. In contrast, SERDs mediate the destabilization of the ER to abolish ER signaling [21]. In addition to these modulators of the ER, drugs that block estrogen synthesis, such as aromatase inhibitors and luteinizing hormone-releasing agonists, are used for breast cancer treatment [20]. Although endocrine therapies are initially successful, breast cancers eventually acquire resistance to these therapies [22,23]. Moreover, patients with basal-like or triple-negative breast cancer (TNBC) exhibit poor outcomes, because this subtype lacks the expression of ER, PR, and HER2, and its effective therapeutic targets remain unidentified. Furthermore, metastatic breast cancer is considered incurable with the therapies available currently [1,24]. Thus, novel therapeutic targets and biomarkers are urgently needed. Recent studies have shown that lncRNAs play important roles in the pathophysiology of various cancers, including breast cancer, suggesting the potential of lncRNAs in developing novel strategies of cancer treatment [9,10].

3. LncRNAs

Together with the advancement of technologies of cDNA cloning and RNA sequencing, ~70–90% of mammalian genomes are shown to be transcribed to produce huge numbers of noncoding RNAs (ncRNAs), while less than 3% of these genomes are translated to proteins, suggesting the importance of ncRNAs in biological processes [25,26,27]. ncRNAs are classified by their length, i.e., ncRNAs shorter than 200 nucleotides are classified as small ncRNAs, while longer ncRNAs are defined as lncRNAs. MicroRNAs (miRNAs) belong to the small ncRNA category and are involved in translational repression and mRNA destabilization in cooperation with various proteins, including argonaute (AGO) proteins [28]. As it has been shown that miRNAs play key roles in numerous biological processes and diseases, including various types of cancers, their clinical application has been studied [10,29]. Moreover, lncRNAs have been suggested to be essential for cell physiology. Previous studies have identified a large number of lncRNA genes in mammals. For example, the GENCODE project, which is part of the ENCODE project and aims to annotate all gene features in the mouse and human genomes, has identified 13,197 and 17,952 lncRNA genes in mice and humans, respectively [30]. Moreover, a previous transcriptome study reported 58,648 lncRNA genes in humans [5]. Although most lncRNAs remain to be studied, it has been gradually elucidated that some lncRNAs play important roles in multiple biological phenomena, such as cell differentiation and organogenesis and diseases [6,7,8]. The expression of lncRNAs tends to be highly cell type- and tissue-specific [3], implying that lncRNAs are good candidate biomarkers and therapeutic targets for diseases. Intriguingly, the expression of some lncRNAs is deregulated in cancers, and these lncRNAs exert oncogenic or tumor-suppressive functions via various mechanisms, such as regulating the transcription or translation of target genes and modulating signal transduction [9,10]. Furthermore, some lncRNAs are involved in breast cancer progression via controlling some processes of breast cancer pathophysiologies, such as invasion and metastasis, and drug resistance (reviewed in [11]). Thus, lncRNAs may be promising biomarkers and therapeutic targets of cancers, including breast cancer. As mentioned above, endocrine therapy resistance is one of the major therapeutic problems for breast cancer. Intriguingly, some lncRNAs regulate the endocrine therapy resistance of breast cancer, and may be key factors for the treatment of breast cancer with endocrine therapy resistance. In the following sections, we introduce the studies of lncRNAs using models of breast cancer cells that are sensitive or resistant to drugs used for endocrine therapy (e.g., tamoxifen as the SERM, ICI182,780 as the SERD, and anastrozole as the aromatase inhibitor), models of breast cancer cells under LTED conditions, and clinical specimens of breast tumors, and intensely describe the functions and mechanisms of lncRNAs in the endocrine therapy resistance of breast cancer, as revealed by these studies.

4. LncRNAs Involved in the Endocrine Therapy Resistance of Breast Cancer

LncRNAs can be classified into one or more of five categories: (A) sense lncRNAs that overlap the neighboring protein-coding gene on the same strand; (B) antisense lncRNAs that overlap the neighboring protein-coding gene on the opposite strand; (C) bidirectional lncRNAs, which are transcribed from the opposite strand within 1 kb from the nearest protein-coding gene; (D) intronic lncRNAs that are derived wholly from intronic regions of protein-coding genes; or (E) intergenic lncRNAs, or long intergenic noncoding RNAs (lincRNAs) that are transcribed from the genomic interval between two genes (Figure 1) [31]. For example, among the lncRNAs related to the endocrine therapy of breast cancer, HOX transcript antisense RNA (HOTAIR) is classified as an antisense lncRNA, while urothelial cancer associated 1 (UCA1) is a lincRNA. In addition, several endocrine therapy resistance-related lncRNAs belong to multiple categories. In the following section, we introduce lncRNAs involved in the endocrine therapy resistance of breast cancer based on these categories.

4.1. Antisense LncRNAs

The HOTAIR lncRNA enhances resistance to tamoxifen [32]. HOTAIR is a ~2.2 kb lncRNA, and its gene overlaps the homeobox C11 (HOXC11) gene on the opposite strand [33]. A previous study using an ER-positive breast cancer cell line, MCF7, showed that HOTAIR binds to the estrogen receptor α (ERα), and the overexpression of HOTAIR enhances ER signaling by upregulating ERα expression levels and promoting the chromatin binding of the ERα, even under hormone-starved conditions. These results suggest that HOTAIR activates ligand-independent ER signaling, which may contribute to tamoxifen resistance (Figure 2) [32]. Moreover, HOTAIR has been demonstrated to promote breast cancer progression via transcriptional regulation. HOTAIR binds to the polycomb repressive complex 2 (PRC2) with its 5′ side, and regulates the PRC2-mediated trimethylation of H3K27 in trans at the HOXD locus on chromosome 2, which leads to transcriptional repression of the HOXD locus [33]. Furthermore, HOTAIR induces selective re-targeting of PRC2 and trimethylated H3K27 genome-wide, thus promoting the invasion of breast cancer cells [34]. Consistently, high expression of HOTAIR is associated with a short duration of metastasis-free and overall survival in patients with breast cancer [34,35]. Moreover, the 3′ side of HOTAIR binds to corepressor for element-1-silencing transcription factor (CoREST)/repressor element-1 silencing transcription factor (REST) complexes, including lysine-specific demethylase 1 (LSD1), which mediates the demethylation of dimethylated H3K4 (H3K4me2). HOTAIR can bind simultaneously to PRC2 and the LSD1/CoREST/REST complexes, to coordinate the targeting of these complexes to hundreds of genes for coupled H3K27 methylation and H3K4 demethylation [36]. Furthermore, the HOTAIR–LSD1 complex is involved in transcriptional activation mediated by c-Myc. In addition, the hepatitis B X-interacting protein (HBXIP) binds directly to c-Myc on target genes and recruits LSD1 via interaction with HOTAIR, which enhances the transcription of c-Myc target genes, possibly through the LSD1-mediated demethylation of H3K4me2 [37]. HOTAIR, HBXIP, and LSD1 promote breast cancer proliferation, highlighting the function of HOTAIR as a critical effector of c-Myc in cooperation with HBXIP and LSD1 [37]. Thus, HOTAIR plays important roles in the epigenetic regulation of gene expression. However, a recent study has proposed that PRC2 is dispensable for the HOTAIR-mediated trimethylation of H3K27 and gene silencing [38], suggesting that further studies are necessary for elucidating the precise mechanisms by which HOTAIR epigenetically controls gene expression. In addition, HOTAIR acts as a competing endogenous RNA (ceRNA) that specifically sponges the target miRNAs and inhibits their activities. For example, HOTAIR is a ceRNA for miR-206 and increases the expression of a miR-206 target gene, the Bcl-w/Bcl-2 like protein 2 (BCL2L2) gene, thus promoting breast cancer proliferation [39]. Moreover, HOTAIR functions as a ceRNA for miR-20a-5p and upregulates a miR-20a-5p target, the high mobility group AT-hook 2 (HMGA2) gene, which enhances the proliferation, survival, migration, and invasion of breast cancer cells, and the growth of breast tumors [40]. Thus, HOTAIR controls breast cancer progression via multiple pathways of regulation of gene expression.
Thymopoietin antisense transcript 1 (TMPO-AS1) is an lncRNA that was demonstrated recently to enhance tamoxifen resistance in breast cancer [41]. TMPO-AS1 is a ~3.2 kb lncRNA, and its gene overlaps the thymopoietin (TMPO) gene on the opposite strand. High expression of TMPO-AS1 is associated with short distant-metastasis-free and overall survival in patients with breast cancer [41]. In addition, the upregulation of TMPO-AS1 is observed in MCF7-derived, tamoxifen-resistant cells (OHTR) and MCF7-derived LTED cells, which is associated with poor relapse-free survival in patients with breast cancer treated with tamoxifen [41]. TMPO-AS1 is induced by estrogen in MCF7 cells and another ER-positive breast cancer cell line, T47D. The purification experiments of TMPO-AS1 from these cell lines by using its antisense oligonucleotide probes suggest that TMPO-AS1 binds to the 3′ untranslated region (UTR) of the estrogen receptor 1 (ESR1) mRNA, which encodes the ERα protein, through an RNA–RNA interaction. Moreover, this RNA–RNA interaction results in the stabilization of the ESR1 mRNA. Thus, TMPO-AS1 upregulates ESR1 expression and ER signaling pathways, contributing to cell proliferation and tamoxifen resistance (Figure 2) [41]. Therefore, TMPO-AS1 is a promising biomarker and therapeutic target for ER-positive breast cancer. In other cancers, it has been suggested that TMPO-AS1 interacts with RNAs other than the ESR1 mRNA and promotes disease progression [42,43,44]. For example, in cervical cancer, TMPO-AS1 functions as a ceRNA via the sponging of miR-577 and upregulates a miR-577 target, RAB14, to promote cell proliferation, survival, and migration [42]. In osteosarcoma, TMPO-AS1 increases the expression of WNT7B by sponging miR-199a-5p, which promotes cell proliferation and survival [43]. In addition, TMPO-AS1 stabilizes the TMPO mRNA to promote the proliferation, survival, migration, and invasion of non-small cell lung cancer (NSCLC) cells. Mechanistically, TMPO-AS1 may stabilize the TMPO mRNA through their interaction [44]. Thus, TMPO-AS1 exerts oncogenic effects in various cancers by forming RNA duplexes with some target RNAs.
Conversely, the ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9) antisense RNA 2 (ADAMTS9-AS2) lncRNA decreases tamoxifen resistance [45]. ADAMTS9-AS2 is an antisense transcript of the tumor-suppressor ADAMTS9 gene. It has been suggested that low expression of ADAMTS9-AS2 is associated with poor prognosis in patients with several types of cancers, such as lung, colorectal, and gastric cancers, while high ADAMTS9-AS2 expression is associated with poor prognosis in patients with some cancers, such as bladder cancer and salivary adenoid cystic carcinoma [46,47,48,49,50]. ADAMTS9-AS2 is downregulated in tamoxifen-resistant cells derived from MCF7, and downregulation of ADAMTS9-AS2 is also observed in breast cancer tissues, especially in breast tumors with grade III–IV or a tumor size larger than 2 cm [45]. From the knockdown or overexpression experiments of ADAMTS9-AS2 in an MCF7-derived tamoxifen-resistant cell line, it is shown that ADAMTS9-AS2 acts as a ceRNA by sponging miR-130a-5p to promote the expression of a miR-130a-5p target gene, phosphatase and tensin homolog (PTEN), which is a well-known tumor-suppressor and enhances tamoxifen sensitivity (Figure 2) [45].

4.2. LincRNAs

UCA1 is a lincRNA that was originally identified as a transcript that is upregulated in bladder transitional cell carcinoma [51]. UCA1 is downregulated in breast cancer and promotes disease progression [52]. From UCA1 knockdown and overexpression experiments in breast cancer cells, such as MCF7, T47D, and tamoxifen-resistant cells derived from these cells, it has been suggested that UCA1 enhances tamoxifen resistance by activating the mammalian target of rapamycin (mTOR), Wnt/β-catenin, and PI3K/AKT signaling pathways (Figure 3A) [53,54,55]. Moreover, UCA1 is shown to interact with the enhancer of zeste homolog 2 (EZH2), which is a catalytic subunit of the PRC2, and suppress the expression of cell-cycle regulator p21, by promoting the trimethylation of H3K27 on the p21 promoter, thus contributing to tamoxifen resistance (Figure 3A) [55]. In addition, from a previous study using breast cancer cell lines, such as MCF7 and BT474, it is shown that UCA1 acts as a ceRNA by sponging miR-18a to upregulate a target of miR-18a, the hypoxia-inducible factor 1α (HIF1α). As HIF1α activates the transcription of UCA1, UCA1 and HIF1α form a feedback regulatory loop that strengthens tamoxifen resistance (Figure 3A) [56]. Intriguingly, it has been reported that UCA1 is secreted from an MCF7-derived, tamoxifen-resistant cell line, LCC2, by exosomes, and that exosome-mediated UCA1 transfer enhances the tamoxifen resistance of MCF7 cells [57].
Another lincRNA, breast cancer anti-estrogen resistance 4 (BCAR4), was identified in a functional screening of genes regulating the tamoxifen resistance of an ER-positive breast cancer cell line, ZR-75-1 [58]. Further studies suggest that the BCAR4-mediated tamoxifen resistance of ZR-75-1 depends on HER2/ErbB2, ErbB3, and ErbB4, but not ERα, and that BCAR4 overexpression enhances the resistance of MCF7 to antiestrogen ICI182,780 in a HER2/ErbB2-, ErbB3-, and ErbB4-dependent manner. [59,60,61]. BCAR4 interacts with several proteins, such as glioma-associated oncogene family zinc finger 2 (GLI2), smad nuclear interacting protein 1 (SNIP1), and phosphatase 1 nuclear targeting subunit (PNUTS), and regulates C–C motif chemokine ligand 21 (CCL21)-stimulated noncanonical hedgehog signaling pathway [62]. Although this activity of BCAR4 contributes to breast cancer metastasis [62], whether this mechanism is involved in the resistance to tamoxifen and ICI182,780 remains unknown.
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lincRNA that has been suggested to be involved in the tamoxifen resistance of breast cancer [63]. MALAT1 was initially reported as an lncRNA that is highly expressed in stage I NSCLC tumors that subsequently metastasize, and high expression of MALAT1 is associated with short overall survival in patients with NSCLC [64]. Moreover, dysregulation of MALAT1 expression has been indicated in various cancers, including breast cancer [65]. MALAT1 is an ~8.7 kb lincRNA, and its gene is located on human chromosome 11q13.1. The MALAT1 primary transcript contains a tRNA-like structure at the 3′ end [66]. RNase P and RNase Z, which are endonucleases that cleave the 5′ or 3′ side of a tRNA precursor [67,68], cleave both sides of this tRNA-like structure, resulting in the 3′-end maturation of MALAT1 [66]. The excised tRNA-like RNA (MALAT1-associated small cytoplasmic RNA (mascRNA) is added with CCA trinucleotides at the 3′ end and exported to the cytoplasm [66].
Although the function of mascRNA is not well understood, it is suggested that mascRNA is an immune regulator in monocytes that is involved in innate immunity in cardiomyocytes [69]. Moreover, the 3′ end of mature MALAT1 contains two U-rich sequences and the associated A-rich sequences, and these sequences form a triple-helical structure that enhances the stability of MALAT1 [70,71]. MALAT1 is localized in the nucleus, especially in nuclear bodies, which are termed nuclear speckles or SC35 domain and are enriched for splicing factors [72]. Regarding tamoxifen resistance, high expression of MALAT1 is associated with a short recurrence-free survival in patients with ER-positive breast cancer treated with tamoxifen [63]. In addition, high MALAT1 expression is associated with poor recurrence-free survival in patients with ER-negative breast cancer, indicating the importance of the ER-independent functions of MALAT1 [63]. The roles of MALAT1 in breast cancer are complicated, because both oncogenic and tumor-suppressive roles of MALAT1 in breast cancer have been reported. For example, MALAT1 acts as a ceRNA for some miRNAs, such as miR-124, miR-1, miR-129-5p, miR-204, and miR-339-5p, thus promoting breast cancer progression [73,74,75,76,77]. In contrast, MALAT1 functions as a ceRNA for miR-20a to inhibit the growth and metastasis of breast cancer [78]. Moreover, MALAT1 regulates transcriptional and posttranscriptional events in ways other than sponging miRNAs. For instance, MALAT1 interacts with the promoter of the eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) gene and upregulates EEF1A1 expression by enhancing the trimethylation of H3K4, which promotes the proliferation and invasion of breast cancer [79]. In addition, MALAT1 forms a complex with the serine/arginine-rich splicing factor 1 (SRSF1), the inhibitor of the DNA binding 4, HLH protein (ID4), and mutant p53, and regulates the alternative splicing of the vascular endothelial growth factor A (VEGFA) mRNA precursor (pre-mRNA), which increases the angiogenic potential of breast cancer cells [80]. Conversely, MALAT1 binds to an RNA-binding protein, Hu antigen R (HuR), and interacts with the CD133 gene to downregulate CD133, thus suppressing the epithelial-to-mesenchymal transition (EMT) and migration activity of breast cancer cells [81]. Although the mechanisms via which MALAT1 exerts both oncogenic and tumor-suppressive functions are not well understood, its functions may depend on context, such as cell type and environment. Furthermore, the dual roles of MALAT1 in cancer progression have been suggested by studies using Malat1 knockout (KO) mice [82,83]. Arun et al. reported that Malat1 KO suppresses the lung metastasis of mammary tumors generated in mouse mammary tumor virus (MMTV)-polyomavirus middle T antigen (PyMT) mice [82]. Inversely, Kim et al. later demonstrated that Malat1 KO enhances the dissemination and lung metastasis of mammary tumors in MMTV-PyMT mice, and that this phenotype can be rescued by the transgenic expression of Malat1 from the ROSA26 locus [83]. Although it is not clear why there is a discrepancy between those results, it may be partly attributed to differences in the methodology for Malat1 KO. In the former study, Malat1 KO was accomplished by deletion of a ~3 kb genomic region containing the 5′ end of the Malat1 gene and its promoter using Cre-mediated recombination technology, while in the latter study, Malat1 was depleted by inserting the lacZ gene and polyadenylation sequences 69 bp downstream of the transcriptional start site of Malat1. These genomic rearrangements in Malat1 KO mice might affect the chromosomal conformation and some nuclear events of gene expression differently, resulting in differential phenotypes. Based on their findings, the manner in which the expression of lncRNAs is suppressed may be important for elucidating lncRNA functions.
The large intergenic noncoding RNA-regulator of reprogramming (lincRNA-ROR) also upregulates tamoxifen resistance [84,85,86]. LincRNA-ROR was originally identified as an lncRNA that is upregulated in induced pluripotent stem cells (iPSCs) compared with embryonic stem cells (ESCs), and has been shown to modulate reprogramming [87]. LincRNA-ROR promotes the proliferation and invasion of MCF7 and a TNBC cell line, MDA-MB-231, by regulating the TGF-β signaling pathway, and high expression of lincRNA-ROR is associated with a poor prognosis in patients with breast cancer [88]. Regarding the mechanisms by which lincRNA-ROR regulates tamoxifen resistance, lincRNA-ROR knockdown experiments in BT474 suggest that lincRNA-ROR enhances tamoxifen resistance by inhibiting autophagy (Figure 3B) [85]. In addition, a previous study using lincRNA-ROR-KO MCF7 cells suggests that lincRNA-ROR promotes the degradation of an extracellular signal-regulated kinase (ERK)-specific phosphatase—the dual specificity phosphatase 7 (DUSP7)—under estrogen-deprived conditions, which results in the ligand-independent activation of ERα mediated by the mitogen-activated protein kinase (MAPK)/ERK signaling pathway. As a result, lincRNA-ROR promotes estrogen-independent growth and tamoxifen resistance in breast cancer (Figure 3B) [86]. Moreover, from a previous study using an MCF7-derived tamoxifen-resistant cell line, lincRNA-ROR is suggested to act as a ceRNA by sponging miR-205-5p to upregulate the miR-205-5p target zinc finger E-box binding homeobox 1/2 (ZEB1/2), thus enhancing EMT and tamoxifen resistance (Figure 3B) [84]. In MDA-MB-231, lincRNA-ROR acts as a ceRNA for another miRNA, miR-145, to upregulate its targets, i.e., ADP ribosylation factor 6 (ARF6) and mucin 1, which control the subcellular localization of E-cadherin and the metastasis of TNBC [89,90]. In addition to these findings, the genotypes of the rs4801078 SNP in lincRNA-ROR are associated with the risk of breast cancer [91], suggesting that lincRNA-ROR is both a promising biomarker and a therapeutic target of breast cancer.
Furthermore, the lincRNA termed lncRNA in non-homologous end joining (NHEJ) pathway 1 (LINP1) enhances tamoxifen resistance [92]. LINP1 was initially identified as an lncRNA that is highly expressed in TNBC. In TNBC, LINP1 forms a complex with Ku autoantigen, 80kDa (Ku80) and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and activates the NHEJ pathway, which repairs double-stranded breaks in DNA [93]. Consistent with these findings, LINP1 enhances the resistance to radiation and chemotherapeutic drugs that cause DNA damage, such as 5-fluorouracil and doxorubicin [93,94]. LINP1 also promotes the proliferation of ER-positive MCF7 breast cancer cells [94]. In addition, LINP1 expression is negatively regulated by estrogen, and is upregulated in ER-positive breast cancer cell lines, MCF7 and T47D, under estrogen-deprived or tamoxifen-treated conditions, as well as in tamoxifen-resistant breast cancer cells derived from these cell lines [92]. From the knockdown and overexpression experiments of LINP1 in MCF7 and T47D, it is suggested that LINP1 inhibits the ER signaling pathway by downregulating ERα, which may be involved in tamoxifen resistance [92].
Recently, it has been reported that the cytoskeleton regulator (CYTOR)/LINC00152 lincRNA is involved in tamoxifen resistance [95]. CYTOR promotes the proliferation and migration of breast cancer cells, and high expression of CYTOR is associated with relapse-free survival in patients with breast cancer. CYTOR regulates the epidermal growth factor receptor and mTOR signaling pathways and control the organization of the filamentous actin cytoskeleton [96]. Moreover, CYTOR is upregulated in tamoxifen-resistant breast cancer cell lines derived from MCF7, and CYTOR functions as a ceRNA by sponging miR-125a-5p, and upregulates a target of miR-125a-5p, the serum response factor (SRF), which promotes the tamoxifen resistance and cell proliferation [95]. Consistent with these data, CYTOR expression is higher in breast tumors from tamoxifen-resistant patients [95]. In addition, CYTOR is associated with poor prognosis in patients with TNBC, and induces the ubiquitination-mediated degradation of PTEN in TNBC [97].
Although there few studies have addressed lncRNAs that regulate the resistance to aromatase inhibitors, there is some evidence of this phenomenon. The lncRNA MIR2052HG lincRNA enhances the resistance to aromatase inhibitors [98,99]. LncRNA MIR2052HG is a ~2 kb lncRNA, and its gene is located on human chromosome 8q21.11–q21.13. This lncRNA upregulates the expression of ERα. From the knockdown experiments of MIR2052HG in ER-positive CAMA-1 cells, MCF7 cells stably transfected with the cytochrome P450 family 19 subfamily A member 1 (CYP19A1) gene that is an aromatase inhibitor target, and MCF7-derived cells resistant to an aromatase inhibitor anastrozole, it has been shown that MIR2052HG increases the expression level of the lemur tyrosine kinase 3 (LMTK3), which in turn regulates the expression of both ESR1 mRNA and ERα protein, and contributes to the resistance to anastrozole (Figure 3C) [99,100]. For regulating the ESR1 mRNA, LMTK3 decreases the activity of protein kinase C (PKC), which suppresses Ser 473 phosphorylation and the activation of AKT mediated by PKC. As AKT phosphorylates and induces the proteasome-mediated degradation of forkhead box O3 (FOXO3), a transcription factor that controls ESR1 expression, the MIR2052HG/LMTK3/PKC/AKT axis stabilizes FOXO3, thus upregulating ESR1 transcription [99,100]. Conversely, LMKT3 suppresses the activity of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK/ribosomal S6 kinase 1 (RSK1) signaling pathway through the downregulation of PKC activity, which results in a decrease in the Ser 167 phosphorylation level of ERα as well as its stabilization (Figure 3C) [99,100]. In addition, single-nucleotide polymorphisms (SNPs) located near or within the MIR2052HG gene locus are associated with the recurrence of breast cancer in patients treated with aromatase inhibitors as adjuvant therapy, suggesting that these SNPs in MIR2052HG are promising biomarkers that can be used to identify patients in whom aromatase inhibitors would be an appropriate therapy [98].
Moreover, a recent study indicated that the lncRNA LINC00309 is associated with poor disease-free survival in patients with breast cancer treated with endocrine therapy using aromatase inhibitors, which suggests that LINC00309 plays important roles in the acquisition of resistance to these therapeutic agents [101].

4.3. LncRNAs Belonging to Multiple Categories

The growth-arrest specific 5 (GAS5) lncRNA is downregulated in tamoxifen-resistant breast cancer cells, and low GAS5 expression enhances resistance to tamoxifen [102]. GAS5 was originally isolated as a gene that is preferentially expressed in growth-arrested NIH3T3 cells [103]. The GAS5 gene has two alternative promoters, as well as multiple exons and introns. As alternative choices of these exons and alternative promoter usage produce multiple GAS5 variants, GAS5 can be defined as an antisense lncRNA overlapping a protein-coding gene, the zinc finger and BTB domain containing 37 (ZBTB37) gene, on the opposite strand or as a bidirectional lncRNA [104]. GAS5 is a host gene of a class of small　noncoding RNAs termed box C/D small nucleolar RNAs (SNORDs); 10 SNORDs are encoded within the GAS5 intronic regions [104]. These snoRNAs are transcribed as part of the GAS5 primary transcript, and are then excised and matured. Regarding endocrine therapy resistance, a previous study using an MCF7-derived tamoxifen-resistant cell line suggests that GAS5 acts as a ceRNA by sponging miR-222 and upregulates PTEN, which is a target of miR-222 and weakens the tamoxifen resistance of breast cancer cells (Figure 4) [102].
In addition to downregulating tamoxifen resistance, GAS5 exerts tumor-suppressive effects in breast cancer via several pathways. For example, GAS5 acts as a ceRNA by sponging miR-21 and upregulates the expression of miR-21 targets programmed cell death 4 (PCDC4) and PTEN, both of which are tumor-suppressor genes [105]. Moreover, GAS5 acts as a ceRNA for miR-196a-5p and downregulates the forkhead box O1 (FOXO1)/phosphoinositide 3-kinase (PI3K)/AKT pathway, thus suppressing the invasion of TNBC cells [106]. In addition to its functions as a ceRNA, GAS5 is involved in transcriptional regulation. GAS5 suppresses glucocorticoid-induced transcription and sensitizes breast cancer cells to apoptosis [107,108]. Exon 12 of GAS5 contains a hairpin structure with two sequences similar to the GR target sequence, termed glucocorticoid response element (GRE). This hairpin structure is called the GAS5 GRE-mimic, and it interacts directly with the DNA-binding domain of GR and suppresses the transcriptional activation of GR target genes, including antiapoptotic genes like cellular inhibitor of apoptosis 2 (cIAP2) and serum- and glucocorticoid-regulated kinase 1 (SGK1), which facilitate stress-inducible apoptosis [107]. In addition to the GR, GAS5 and the GAS5 GRE-mimic bind to other 3-keto steroid receptors, such as the mineralocorticoid, progesterone, and androgen receptors, and inhibit their transcriptional activities [107,108]. Interestingly, the GAS5 GRE-mimic alone can increase apoptosis in breast cancer cells, suggesting that the oligonucleotides of the GRE-mimic may be applicable to breast cancer therapy [108]. Consistent with these findings, GAS5 is downregulated in breast tumors compared with normal tissues, and low expression of GAS5 is associated with poor overall survival in patients with breast cancer and TNBC [102,104,106]. Moreover, a recent study showed that an insertion (ins)/deletion (del) polymorphism located within the GAS5 promoter (rs145204276 AGGCA/–) affects the risk of breast cancer [109]. In that study, the rs145204276 ins/del and del/del genotypes, as well as the del allele, were associated with a reduced risk of breast cancer [109]. As GAS5 expression is significantly higher in patients with breast cancer carrying the rs145204276 ins/del and del/del genotypes versus the rs145204276 ins/ins genotype carriers, and since the rs145204276 del allele increases the transcription of GAS5, this polymorphism may affect the risk of breast cancer by modulating GAS5 expression levels [109].
The Down syndrome cell adhesion molecule antisense RNA 1 (DSCAM-AS1) is an intronic antisense lncRNA that is transcribed from the opposite strand of the Down syndrome cell adhesion molecule (DSCAM) gene, and is wholly derived from the intronic region of DSCAM. DSCAM-AS1 promotes tamoxifen resistance [110,111] and is upregulated in breast cancer tissues compared with normal tissues [110,112]. Moreover, DSCAM-AS1 expression is higher in luminal and HER2-positive breast cancers, and particularly in the luminal B subtype [110,112]. Importantly, previous studies have demonstrated that DSCAM-AS1 is an ERα target gene [110,112], and is important for cell proliferation and the invasion of MCF7 and T47D cells [110,112,113], as well as for the growth and liver metastasis of T47D cells xenografted into immunodeficient mice [110]. Moreover, DSCAM-AS1 expression is elevated in tamoxifen-resistant breast cancer tissues, and the knockdown and overexpression experiments of DSCAM-AS1 in breast cancer cell lines, such as MCF7 and T47D, suggest that DSCAM-AS1 promotes tamoxifen resistance [110,111]. Consistent with these results, a high expression of DSCAM-AS1 has been associated with a short disease-free survival for patients with luminal breast cancer and those with luminal breast cancer treated with endocrine therapy [113]. Although the manner in which DSCAM-AS1 functions in breast cancers remains unclear, the RNA-binding protein heterogeneous nuclear ribonucleoprotein L (hnRNPL) is required for DSCAM-AS1 activity in MCF7 and T47D cells [110]. DSCAM-AS1 interacts with hnRNPL via its 3′ region, which contains CACA-rich RNA sequences [110]. Furthermore, a previous study using MCF7-derived, tamoxifen-resistant cells suggests that DSCAM-AS1 acts as a ceRNA by sponging miR-137, which increases the expression of epidermal growth factor receptor pathway substrate 8 (EPS8), thus contributing to tamoxifen resistance (Figure 4) [111]. In addition, it was reported recently that DSCAM-AS1 functions as a ceRNA for miR-204-5p in the breast cancer susceptibility gene 1 (BRCA1)-mutated TNBC cell line HCC1937, to promote tumor growth via the upregulation of ribonucleotide reductase M2 (RRM2) [114].
ESR1 locus enhancing and activating noncoding RNAs (Eleanors) were identified as a group of lncRNAs that are transcribed from inside and around the ESR1 locus, and could consist of lncRNAs of all categories [115]. Previous studies have shown that Eleanors play important roles in ER-positive breast cancer progression under estrogen-deprived conditions. Eleanors are specifically expressed in ER-positive breast cancer tissues and MCF7 cells, and are increased in MCF7 cells cultured under LTED conditions [115]. u-Eleanor is an Eleanor that is transcribed from ~40 kb upstream of the canonical promoter of ESR1 and upregulates the transcription of the ESR1 mRNA and other Eleanors to promote the proliferation of LTED cells (Figure 4) [115]. A chromatin immunoprecipitation-sequencing (ChIP-seq) analysis showed that the u-Eleanor locus in LTED cells is enriched for monomethylated H3K4, rather than trimethylated H3K4, suggesting that the u-Eleanor locus functions as an enhancer. Clinically, the upregulation of u-Eleanor has been reported to be negatively associated with increasing breastfeeding duration [116]. u-Eleanor tends to be upregulated in healthy women without a history of breastfeeding and women with a breastfeeding duration of 1–6 months. Epidemiological studies have demonstrated that breastfeeding experiences play a protective role against breast cancer in women, while a lack or a short duration of breastfeeding increases breast cancer risk [117,118,119]. Therefore, u-Eleanor may be used as a biomarker of breast cancer at early stages [116]. Furthermore, a recent study has revealed the function of another Eleanor called promoter-associated Eleanor (pa-Eleanor), which is transcribed from the region proximal to the transcriptional start site of ESR1 [120]. In the nucleus, chromosomes fold into domains called topologically associating domains (TADs), which exhibit intra-chromatin interactions [121]. The chromosome conformation capture combined with high-throughput sequencing (4C-seq) analysis, reported in a recent study, reveals that a TAD including Eleanor-expressing regions (Eleanor TAD) resides on human chromosome 6q25.1, and that Eleanor TAD contains the ESR1 gene and three other genes: coiled-coil domain containing 170 (CCDC170), chromosome 6 open reading frame 211 (C6orf211), and required for meiotic nuclear division 1 homolog (RMND1) [120]. pa-Eleanor upregulates genes within Eleanor TAD and promotes the proliferation of LTED cells (Figure 4). In addition, pa-Eleanor upregulates u-Eleanor, whereas u-Eleanor does not affect pa-Eleanor expression, suggesting that pa-Eleanor upregulates the transcription of the ESR1 mRNA through u-Eleanor [120]. Moreover, pa-Eleanor enhances an intra-chromosomal interaction between the ESR1 promoter region and the region near the FOXO3 locus on human chromosome 6q21 [120]. This chromosomal interaction may affect the expression of genes within Eleanor TAD. FOXO3 is a transcription factor that induces apoptosis through the transcriptional regulation of apoptosis-associated genes, and its expression is elevated in LTED cells. The knockdown of pa-Eleanor decreases ESR1 expression levels (but does not affect the expression of FOXO3) and induces the apoptosis of LTED cells. Therefore, pa-Eleanor may promote the survival of LTED cells by regulating the balanced expression of ESR1 and FOXO3 [120]. Thus, the functions of u-Eleanor and pa-Eleanor suggest that the regulation of Eleanor expression may represent a new treatment strategy for breast cancer adapted to estrogen-deprived conditions. Consistent with this idea, resveratrol and glyceollin I, phytoalexins that are synthesized in plants under stress conditions, decrease the expression of Eleanors to induce apoptotic death in LTED cells [122].
In addition to these lncRNAs, recent gene expression analysis in patients with ER-positive breast cancer, who were primarily treated with tamoxifen, identified 11 lncRNAs, belonging to multiple categories (PINK1-AS, RP11-259N19.1, KLF3-AS1, LINC00339, LINC00472, RP11-351I21.11, KB-1460A1.5, PKD1P6-NPIPP1, PDCD4-AS1, PP14571, and RP11-69E11.4), as prognostic lncRNAs that predict the risk of systemic relapse [123]. PINK1-AS, RP11-259N19.1, KLF3-AS1, PDCD4-AS1, PP14571, and RP11-69E11.4 are antisense lncRNAs, while LINC00339, LINC00472, RP11-351I21.11, and KB-1460A1.5 are lincRNAs. PKD1P6-NPIPP1 is a read-through transcript derived from two pseudogenes, polycystin 1, transient receptor potential channel interacting pseudogene 6 (PKD1P6) and nuclear pore complex interacting protein pseudogene 1 (NPIPP1), and classified as an intronic antisense lncRNA, because PKD1P6-NPIPP1 is wholly derived from the opposite strand of the intronic region of the pyridoxal dependent decarboxylase domain containing 1 (PDXDC1) gene. Although the mechanisms by which these 11 lncRNAs are involved in tamoxifen resistance and systemic relapse are unclear, several relapse- or metastasis-related pathways, such as the PI3K/AKT and Wnt signaling pathways, are upregulated in patients with breast cancer who have a high relapse risk predicted by the expression levels of these lncRNAs. Thus, it suggests that these signaling pathways may play important roles in the functions of the 11 prognostic lncRNAs [123].

5. Antisense Oligonucleotides (ASOs) in Clinical Use

Considering that lncRNAs play essential roles in endocrine therapy resistance, intervention against lncRNAs may be promising for breast cancer treatment. Antisense oligonucleotides (ASOs) are used for regulating the stability and activity of RNAs. Some chemically modified ASOs targeting transcripts of protein-coding genes have been approved for clinical use by the U.S. Food and Drug Administration (FDA) [124]. For example, a 2′-O-(2-methoxyethyl) (MOE) phosphorothioate (PS) ASO called nusinersen is used for the treatment of spinal muscular atrophy (SMA). [125,126]. SMA is an autosomal-recessive neuromuscular disorder with degeneration of the motor neurons in the anterior horn of the spinal cord, leading to atrophy of the voluntary muscles of the limbs and trunk [125]. SMA is caused by deletions or loss-of-function mutations of survival of motor neuron 1, telomeric (SMN1) gene and the consequent reduced expression of survival of motor neuron (SMN) proteins from SMN1 transcripts. Although there is a homologue of SMN1 gene called survival of motor neuron 2, centromeric (SMN2), SMN proteins are not efficiently produced from SMN2 transcripts. The SMN2 gene has an identical coding sequence but differs from SMN1 gene by 11 nucleotides. The different sequences between these genes contain a C-to-T mutation on exon 7, which is a synonymous mutation but affects SMN protein expression by promoting the skipping of exon 7. Due to this mutation, 80%–90% of SMN2 mRNAs lack exon 7 and are translated into truncated SMN proteins, which are rapidly degraded (Figure 5A). Therefore, the SMN2 gene does not fully compensate for the loss-of-function of the SMN1 gene [125], and modulating the splicing pattern of SMN2 pre-mRNA to produce the full-length SMN proteins is one of therapeutic strategies of SMA. Nusinersen is an ASO complementary to a site within intron 7 of the SMN2 pre-mRNA called intronic splicing silencer-N1 (ISS-N1), which is involved in the skipping of exon 7 and blocks the activity of ISS-N1 to facilitate the inclusion of the exon 7, resulting in the synthesis of the functional, full-length SMN proteins and the rescue of motor neurons (Figure 5A) [124,125]. Another oligonucleotide drug, mipomersen, is used to treat homozygous familial hypercholesterolemia, an autosomal disorder of the lipid metabolism characterized by elevated levels of low-density lipoprotein (LDL) cholesterol [124,127]. Mipomersen targets the transcripts of the apolipoprotein B (APOB) gene. The middle region of mipomersen shows DNA-like properties and induces the cleavage of these transcripts mediated by ribonuclease H (RNase H), which cleaves RNAs that form heteroduplexes with DNA. As the apoB-100 protein, encoded by APOB gene, is a component of LDL cholesterol, mipomersen-mediated downregulation of APOB decreases the circulating levels of LDL cholesterol (Figure 5B) [123,126,128]. In addition to ASOs, a small interfering RNA (siRNA)-based drug, patisiran, was recently approved by the FDA [124]. Therefore, the targeting lncRNAs with ASOs and siRNAs may be translated into new therapies for breast cancer.

6. Conclusions

In this review, we describe the functions and mechanisms of lncRNAs related to the endocrine therapy resistance of breast cancer (Table 1), and their potential as therapeutic targets. Additionally, LncRNAs may hold promise as biomarkers of breast cancer. Importantly, the quantification of the prostate cancer antigen 3 (PCA3) lncRNA in urine samples has been developed as a diagnostic test for prostate cancer [129], suggesting that lncRNAs may be applicable to the analysis of non-invasive liquid biopsies for the diagnosis of cancers, including breast cancer. Thus, lncRNAs are potential key factors in the development of new strategies of breast cancer treatment, and further studies of lncRNAs in the context of breast cancer are required.

Author Contributions

Conceptualization, T.T. and S.I.; writing—original draft preparation, T.T.; writing—review and editing, K.I., Y.M., K.H.-I., and S.I.; supervision, S.I. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Support Project of Strategic Research Center in Private Universities from the Ministry of Education, Culture, Sports, Science and Technology (MEXT); grants from the Japan Society for the Promotion of Science (15K15353 to S.I. and 17H04205 to K.H.-I.); and Practical Research for Innovative Cancer Control (JP18ck0106194 to K.I.), and Project for Cancer Research and Therapeutic Evolution (P-CREATE, JP18cm0106144 to S.I.) from the Japan Agency for Medical Research and Development (AMED).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Harbeck, N.; Gnant, M. Breast cancer. Lancet 2017, 389, 1134–1150. [Google Scholar] [CrossRef]
  2. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Cabili, M.N.; Trapnell, C.; Goff, L.; Koziol, M.; Tazon-Vega, B.; Regev, A.; Rinn, J.L. Integrative Annotation of Human Large Intergenic Noncoding RNAs Reveals Global Properties and Specific Subclasses. Genes Dev. 2011, 25, 1915–1927. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Derrien, T.; Johnson, R.; Bussotti, G.; Tanzer, A.; Djebali, S.; Tilgner, H.; Guernec, G.; Martin, D.; Merkel, A.; Knowles, D.G.; et al. The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Res. 2012, 22, 1775–1789. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Iyer, M.K.; Niknafs, Y.S.; Malik, R.; Singhal, U.; Sahu, A.; Hosono, Y.; Barrette, T.R.; Prensner, J.R.; Evans, J.R.; Zhao, S.; et al. The landscape of long noncoding RNAs in the human transcriptome. Nat. Genet. 2015, 47, 199–208. [Google Scholar] [CrossRef] [PubMed]
  6. Hu, W.; Alvarez-Dominguez, J.R.; Lodish, H.F. Regulation of mammalian cell differentiation by long non-coding RNAs. EMBO Rep. 2012, 13, 971–983. [Google Scholar] [CrossRef] [Green Version]
  7. Grote, P.; Herrmann, B.G. Long noncoding RNAs in organogenesis: making the difference. Trends Genet. 2015, 31, 329–335. [Google Scholar] [CrossRef] [Green Version]
  8. Perry, R.B.; Ulitsky, I. The functions of long noncoding RNAs in development and stem cells. Development 2016, 143, 3882–3894. [Google Scholar] [CrossRef] [Green Version]
  9. Arun, G.; Diermeier, S.D.; Spector, D.L. Therapeutic Targeting of Long Non-Coding RNAs in Cancer. Trends Mol. Med. 2018, 24, 257–277. [Google Scholar] [CrossRef]
  10. Slack, F.J.; Chinnaiyan, A.M. The Role of Non-coding RNAs in Oncology. Cell 2019, 179, 1033–1055. [Google Scholar] [CrossRef]
  11. Yousefi, H.; Maheronnaghsh, M.; Molaei, F.; Mashouri, L.; Reza Aref, A.; Momeny, M.; Alahari, S.K. Long noncoding RNAs and exosomal lncRNAs: classification, and mechanisms in breast cancer metastasis and drug resistance. Oncogene 2020, 39, 953–974. [Google Scholar] [CrossRef] [PubMed]
  12. Perou, C.M.; Sørlie, T.; Eisen, M.B.; van de Rijn, M.; Jeffrey, S.S.; Rees, C.A.; Pollack, J.R.; Ross, D.T.; Johnsen, H.; Akslen, L.A.; et al. Molecular portraits of human breast tumours. Nature 2000, 406, 747–752. [Google Scholar] [CrossRef] [PubMed]
  13. Sørlie, T.; Perou, C.M.; Tibshirani, R.; Aas, T.; Geisler, S.; Johnsen, H.; Hastie, T.; Eisen, M.B.; van de Rijn, M.; Jeffrey, S.S.; et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 2001, 98, 10869–10874. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Yersal, O.; Barutca, S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J. Clin. Oncol. 2014, 5, 412–424. [Google Scholar] [CrossRef]
  15. Hilton, H.N.; Clarke, C.L.; Graham, J.D. Estrogen and progesterone signalling in the normal breast and its implications for cancer development. Mol. Cell. Endocrinol. 2018, 466, 2–14. [Google Scholar] [CrossRef]
  16. Brisken, C. Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nat. Rev. Cancer 2013, 13, 385–396. [Google Scholar] [CrossRef]
  17. Renoir, J.M.; Marsaud, V.; Lazennec, G. Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem. Pharmacol. 2013, 85, 449–465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Leonhardt, S.A.; Boonyaratanakornkit, V.; Edwards, D.P. Progesterone receptor transcription and non-transcription signaling mechanisms. Steroids 2003, 68, 761–770. [Google Scholar] [CrossRef]
  19. Gao, X.; Nawaz, Z. Progesterone receptors—animal models and cell signaling in breast cancer: Role of steroid receptor coactivators and corepressors of progesterone receptors in breast cancer. Breast Cancer Res. 2002, 4, 182–186. [Google Scholar] [CrossRef]
  20. Reinbolt, R.E.; Mangini, N.; Hill, J.L.; Levine, L.B.; Dempsey, J.L.; Singaravelu, J.; Koehler, K.A.; Talley, A.; Lustberg, M.B. Endocrine Therapy in Breast Cancer: The Neoadjuvant, Adjuvant, and Metastatic Approach. Semin. Oncol. Nurs. 2015, 31, 146–155. [Google Scholar] [CrossRef]
  21. Patel, H.K.; Bihani, T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol. Ther. 2018, 186, 1–24. [Google Scholar] [CrossRef] [PubMed]
  22. Pan, H.; Gray, R.; Braybrooke, J.; Davies, C.; Taylor, C.; McGale, P.; Peto, R.; Pritchard, K.I.; Bergh, J.; Dowsett, M.; et al. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N. Engl. J. Med. 2017, 377, 1836–1846. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. AlFakeeh, A.; Brezden-Masley, C. Overcoming endocrine resistance in hormone receptor–positive breast cancer. Curr. Oncol. 2018, 25, S18–S27. [Google Scholar] [CrossRef] [Green Version]
  24. McDonald, E.S.; Clark, A.S.; Tchou, J.; Zhang, P.; Freedman, G.M. Clinical Diagnosis and Management of Breast Cancer. J. Nucl. Med. 2016, 57 Suppl 1, 9S–16S. [Google Scholar] [CrossRef] [Green Version]
  25. Carninci, P.; Kasukawa, T.; Katayama, S.; Gough, J.; Frith, M.C.; Maeda, N.; Oyama, R.; Ravasi, T.; Lenhard, B.; et al.; The FANTOM Consortium The Transcriptional Landscape of the Mammalian Genome. Science 2005, 309, 1559–1563. [Google Scholar] [CrossRef] [Green Version]
  26. Djebali, S.; Davis, C.A.; Merkel, A.; Dobin, A.; Lassmann, T.; Mortazavi, A.; Tanzer, A.; Lagarde, J.; Lin, W.; Schlesinger, F.; et al. Landscape of transcription in human cells. Nature 2012, 489, 101–108. [Google Scholar] [CrossRef]
  27. Kashi, K.; Henderson, L.; Bonetti, A.; Carninci, P. Discovery and functional analysis of lncRNAs: Methodologies to investigate an uncharacterized transcriptome. Biochim. Biophys. Acta (BBA)-Gene Regul. Mech. 2016, 1859, 3–15. [Google Scholar] [CrossRef] [Green Version]
  28. Iwakawa, H.O.; Tomari, Y. The Functions of MicroRNAs: mRNA Decay and Translational Repression. Trends Cell Biol. 2015, 25, 651–665. [Google Scholar] [CrossRef]
  29. Rupaimoole, R.; Slack, F.J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 2017, 16, 203–222. [Google Scholar] [CrossRef]
  30. GENCODE. Available online: https://www.gencodegenes.org/ (accessed on 31 March 2020).
  31. Ponting, C.P.; Oliver, P.L.; Reik, W. Evolution and Functions of Long Noncoding RNAs. Cell 2009, 136, 629–641. [Google Scholar] [CrossRef] [Green Version]
  32. Xue, X.; Yang, Y.A.; Zhang, A.; Fong, K.W.; Kim, J.; Song, B.; Li, S.; Zhao, J.C.; Yu, J. LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene 2016, 35, 2746–2755. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Rinn, J.L.; Kertesz, M.; Wang, J.K.; Squazzo, S.L.; Xu, X.; Brugmann, S.A.; Goodnough, L.H.; Helms, J.A.; Farnham, P.J.; Segal, E.; et al. Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs. Cell 2007, 129, 1311–1323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Gupta, R.A.; Shah, N.; Wang, K.C.; Kim, J.; Horlings, H.M.; Wong, D.J.; Tsai, M.C.; Hung, T.; Argani, P.; Rinn, J.L.; et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 2010, 464, 1071–1076. [Google Scholar] [CrossRef] [PubMed]
  35. Rajagopal, T.; Talluri, S.; Akshaya, R.L.; Dunna, N.R. HOTAIR LncRNA: A novel oncogenic propellant in human cancer. Clin. Chim. Acta 2020, 503, 1–18. [Google Scholar] [CrossRef] [PubMed]
  36. Tsai, M.C.; Manor, O.; Wan, Y.; Mosammaparast, N.; Wang, J.K.; Lan, F.; Shi, Y.; Segal, E.; Chang, H.Y. Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes. Science 2010, 329, 689–693. [Google Scholar] [CrossRef] [Green Version]
  37. Li, Y.; Wang, Z.; Shi, H.; Li, H.; Li, L.; Fang, R.; Cai, X.; Liu, B.; Zhang, X.; Ye, L. HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc. Cancer Res. 2016, 76, 293–304. [Google Scholar] [CrossRef] [Green Version]
  38. Portoso, M.; Ragazzini, R.; Brenčič, Ž; Moiani, A.; Michaud, A.; Vassilev, I.; Wassef, M.; Servant, N.; Sargueil, B.; Margueron, R. PRC 2 is dispensable for HOTAIR -mediated transcriptional repression. EMBO J. 2017, 36, 981–994. [Google Scholar] [CrossRef]
  39. Ding, W.; Ren, J.; Ren, H.; Wang, D. Long Noncoding RNA HOTAIR Modulates MiR-206-mediated Bcl-w Signaling to Facilitate Cell Proliferation in Breast Cancer. Sci. Rep. 2017, 7, 17261. [Google Scholar] [CrossRef] [Green Version]
  40. Zhao, W.; Geng, D.; Li, S.; Chen, Z.; Sun, M. LncRNA HOTAIR influences cell growth, migration, invasion, and apoptosis via the miR-20a-5p/HMGA2 axis in breast cancer. Cancer Med. 2018, 7, 842–855. [Google Scholar] [CrossRef]
  41. Mitobe, Y.; Ikeda, K.; Suzuki, T.; Takagi, K.; Kawabata, H.; Horie-Inoue, K.; Inoue, S. ESR1-Stabilizing Long Noncoding RNA TMPO-AS1 Promotes Hormone-Refractory Breast Cancer Progression. Mol. Cell. Biol. 2019, 39, e00261-19. [Google Scholar] [CrossRef]
  42. Yang, J.; Liang, B.; Hou, S. TMPO-AS1 promotes cervical cancer progression by upregulating RAB14 via sponging miR-577. J. Gene Med. 2019, 21, e3125. [Google Scholar] [CrossRef] [PubMed]
  43. Cui, H.; Zhao, J. LncRNA TMPO-AS1 serves as a ceRNA to promote osteosarcoma tumorigenesis by regulating miR-199a-5p/WNT7B axis. J. Cell. Biochem. 2020, 121, 2284–2293. [Google Scholar] [CrossRef] [PubMed]
  44. Qin, Z.; Zheng, X.; Fang, Y. Long noncoding RNA TMPO-AS1 promotes progression of non-small cell lung cancer through regulating its natural antisense transcript TMPO. Biochem. Biophys. Res. Commun. 2019, 516, 486–493. [Google Scholar] [CrossRef]
  45. Shi, Y.F.; Lu, H.; Wang, H.B. Downregulated lncRNA ADAMTS9-AS2 in breast cancer enhances tamoxifen resistance by activating microRNA-130a-5p. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 1563–1573. [Google Scholar] [CrossRef]
  46. Liu, C.; Yang, Z.; Deng, Z.; Zhou, Y.; Gong, Q.; Zhao, R.; Chen, T. Upregulated lncRNA ADAMTS9-AS2 suppresses progression of lung cancer through inhibition of miR-223-3p and promotion of TGFBR3. IUBMB Life 2018, 70, 536–546. [Google Scholar] [CrossRef] [Green Version]
  47. Li, Q.; Dai, Y.; Wang, F.; Hou, S. Differentially expressed long non-coding RNAs and the prognostic potential in colorectal cancer. Neoplasma 2016, 63, 977–983. [Google Scholar] [CrossRef]
  48. Cao, B.; Liu, C.; Yang, G. Down-regulation of lncRNA ADAMTS9-AS2 contributes to gastric cancer development via activation of PI3K/Akt pathway. Biomed. Pharmacother. 2018, 107, 185–193. [Google Scholar] [CrossRef]
  49. Zhu, N.; Hou, J.; Wu, Y.; Liu, J.; Li, G.; Zhao, W.; Ma, G.; Chen, B.; Song, Y. Integrated analysis of a competing endogenous RNA network reveals key lncRNAs as potential prognostic biomarkers for human bladder cancer. Medicine (Baltimore) 2018, 97, e11887. [Google Scholar] [CrossRef]
  50. Xie, S.; Yu, X.; Li, Y.; Ma, H.; Fan, S.; Chen, W.; Pan, G.; Wang, W.; Zhang, H.; Li, J.; et al. Upregulation of lncRNA ADAMTS9-AS2 Promotes Salivary Adenoid Cystic Carcinoma Metastasis via PI3K/Akt and MEK/Erk Signaling. Mol. Ther. 2018, 26, 2766–2778. [Google Scholar] [CrossRef] [Green Version]
  51. Wang, X.S.; Zhang, Z.; Wang, H.C.; Cai, J.L.; Xu, Q.W.; Li, M.Q.; Chen, Y.C.; Qian, X.P.; Lu, T.J.; Yu, L.Z.; et al. Rapid Identification of UCA1 as a Very Sensitive and Specific Unique Marker for Human Bladder Carcinoma. Clin. Cancer Res. 2006, 12, 4851–4858. [Google Scholar] [CrossRef] [Green Version]
  52. Yao, F.; Wang, Q.; Wu, Q. The prognostic value and mechanisms of lncRNA UCA1 in human cancer. Cancer Manag. Res. 2019, 11, 7685–7696. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Wu, C.; Luo, J. Long Non-Coding RNA (lncRNA) Urothelial Carcinoma-Associated 1 (UCA1) Enhances Tamoxifen Resistance in Breast Cancer Cells via Inhibiting mTOR Signaling Pathway. Med. Sci. Monit. 2016, 22, 3860–3867. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Liu, H.; Wang, G.; Yang, L.; Qu, J.; Yang, Z.; Zhou, X. Knockdown of Long Non-Coding RNA UCA1 Increases the Tamoxifen Sensitivity of Breast Cancer Cells through Inhibition of Wnt/β-Catenin Pathway. PLoS ONE 2016, 11, e0168406. [Google Scholar] [CrossRef] [PubMed]
  55. Li, Z.; Yu, D.; Li, H.; Lv, Y.; Li, S. Long non coding RNA UCA1 confers tamoxifen resistance in breast cancer endocrinotherapy through regulation of the EZH2/p21 axis and the PI3K/AKT signaling pathway. Int. J. Oncol. 2019, 54, 1033–1042. [Google Scholar] [CrossRef]
  56. Li, X.; Wu, Y.; Liu, A.; Tang, X. Long non-coding RNA UCA1 enhances tamoxifen resistance in breast cancer cells through a miR-18a-HIF1α feedback regulatory loop. Tumour Biol. 2016, 37, 14733–14743. [Google Scholar] [CrossRef]
  57. Xu, C.-G.; Yang, M.-F.; Ren, Y.-Q.; Wu, C.-H.; Wang, L.-Q. Exosomes mediated transfer of lncRNA UCA1 results in increased tamoxifen resistance in breast cancer cells. Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 4362–4368. [Google Scholar]
  58. Meijer, D.; van Agthoven, T.; Bosma, P.T.; Nooter, K.; Dorssers, L.C. Functional Screen for Genes Responsible for Tamoxifen Resistance in Human Breast Cancer Cells. Mol. Cancer Res. 2006, 4, 379–386. [Google Scholar] [CrossRef] [Green Version]
  59. Godinho, M.F.; Sieuwerts, A.M.; Look, M.P.; Meijer, D.; Foekens, J.A.; Dorssers, L.C.; van Agthoven, T. Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer. Br. J. Cancer 2010, 103, 1284–1291. [Google Scholar] [CrossRef] [Green Version]
  60. Godinho, M.; Meijer, D.; Setyono-Han, B.; Dorssers, L.C.; van Agthoven, T. Characterization of BCAR4, a novel oncogene causing endocrine resistance in human breast cancer cells. J. Cell. Physiol. 2011, 226, 1741–1749. [Google Scholar] [CrossRef]
  61. Godinho, M.F.; Wulfkuhle, J.D.; Look, M.P.; Sieuwerts, A.M.; Sleijfer, S.; Foekens, J.A.; Petricoin, E.F.; Dorssers, L.C.; van Agthoven, T. BCAR4 induces antioestrogen resistance but sensitises breast cancer to lapatinib. Br. J. Cancer 2012, 107, 947–955. [Google Scholar] [CrossRef] [Green Version]
  62. Xing, Z.; Lin, A.; Li, C.; Liang, K.; Wang, S.; Liu, Y.; Park, P.K.; Qin, L.; Wei, Y.; Hawke, D.H.; et al. lncRNA Directs Cooperative Epigenetic Regulation Downstream of Chemokine Signals. Cell 2014, 159, 1110–1125. [Google Scholar] [CrossRef] [Green Version]
  63. Huang, N.-S.; Chi, Y.-Y.; Xue, J.-Y.; Liu, M.-Y.; Huang, S.; Mo, M.; Zhou, S.-L.; Wu, J. Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) interacts with estrogen receptor and predicted poor survival in breast cancer. Oncotarget 2016, 7, 37957–37965. [Google Scholar] [CrossRef] [Green Version]
  64. Ji, P.; Diederichs, S.; Wang, W.; Böing, S.; Metzger, R.; Schneider, P.M.; Tidow, N.; Brandt, B.; Buerger, H.; Bulk, E.; et al. MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 2003, 22, 8031–8041. [Google Scholar] [CrossRef] [Green Version]
  65. Sun, Y.; Ma, L. New Insights into Long Non-Coding RNA MALAT1 in Cancer and Metastasis. Cancers 2019, 11, 216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Wilusz, J.E.; Freier, S.M.; Spector, D.L. 3′ End Processing of a Long Nuclear-Retained Noncoding RNA Yields a tRNA-like Cytoplasmic RNA. Cell 2008, 135, 919–932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Frank, D.N.; Pace, N.R. RIBONUCLEASE P: Unity and Diversity in a tRNA Processing Ribozyme. Annu. Rev. Biochem. 1998, 67, 153–180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Maraia, R.J.; Lamichhane, T.N. 3′ processing of eukaryotic precursor tRNAs. Wiley Interdiscip. Rev. RNA 2011, 2, 362–375. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Gast, M.; Schroen, B.; Voigt, A.; Haas, J.; Kuehl, U.; Lassner, D.; Skurk, C.; Escher, F.; Wang, X.; Kratzer, A.; et al. Long noncoding RNA MALAT1-derived mascRNA is involved in cardiovascular innate immunity. J. Mol. Cell Biol. 2016, 8, 178–181. [Google Scholar] [CrossRef] [Green Version]
  70. Brown, J.A.; Valenstein, M.L.; Yario, T.A.; Tycowski, K.T.; Steitz, J.A. Formation of triple-helical structures by the 3’-end sequences of MALAT1 and MENβ noncoding RNAs. Proc. Natl. Acad. Sci. USA 2012, 109, 19202–19207. [Google Scholar] [CrossRef] [Green Version]
  71. Wilusz, J.E.; JnBaptiste, C.K.; Lu, L.Y.; Kuhn, C.-D.; Joshua-Tor, L.; Sharp, P.A. A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails. Genes Dev. 2012, 26, 2392–2407. [Google Scholar] [CrossRef] [Green Version]
  72. Hutchinson, J.N.; Ensminger, A.W.; Clemson, C.M.; Lynch, C.R.; Lawrence, J.B.; Chess, A. A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genom. 2007, 8, 39. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Feng, T.; Shao, F.; Wu, Q.; Zhang, X.; Xu, D.; Qian, K.; Xie, Y.; Wang, S.; Xu, N.; Wang, Y.; et al. miR-124 downregulation leads to breast cancer progression via LncRNA-MALAT1 regulation and CDK4/E2F1 signal activation. Oncotarget 2016, 7, 16205–16216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Jin, C.; Yan, B.; Lu, Q.; Lin, Y.; Ma, L. Reciprocal regulation of Hsa-miR-1 and long noncoding RNA MALAT1 promotes triple-negative breast cancer development. Tumour Biol. 2016, 37, 7383–7394. [Google Scholar] [CrossRef]
  75. Zuo, Y.; Li, Y.; Zhou, Z.; Ma, M.; Fu, K. Long non-coding RNA MALAT1 promotes proliferation and invasion via targeting miR-129-5p in triple-negative breast cancer. Biomed. Pharmacother. 2017, 95, 922–928. [Google Scholar] [CrossRef]
  76. Wang, Y.; Zhou, Y.; Yang, Z.; Chen, B.; Huang, W.; Liu, Y.; Zhang, Y. MiR-204/ZEB2 axis functions as key mediator for MALAT1-induced epithelial-mesenchymal transition in breast cancer. Tumour Biol. 2017, 39, 1010428317690998. [Google Scholar] [CrossRef]
  77. Zheng, L.; Zhang, Y.; Fu, Y.; Gong, H.; Guo, J.; Wu, K.; Jia, Q.; Ding, X. Long non-coding RNA MALAT1 regulates BLCAP mRNA expression through binding to miR-339-5p and promotes poor prognosis in breast cancer. Biosci. Rep. 2019, 39, BSR20181284. [Google Scholar] [CrossRef] [Green Version]
  78. Zhao, L.; Zhao, Y.; He, Y.; Li, Q.; Mao, Y. The functional pathway analysis and clinical significance of miR-20a and its related lncRNAs in breast cancer. Cell. Signal. 2018, 51, 152–165. [Google Scholar] [CrossRef]
  79. Li, X.; Chen, N.; Zhou, L.; Wang, C.; Wen, X.; Jia, L.; Cui, J.; Hoffman, A.R.; Hu, J.-F.; Li, W. Genome-wide target interactome profiling reveals a novel EEF1A1 epigenetic pathway for oncogenic lncRNA MALAT1 in breast cancer. Am. J. Cancer Res. 2019, 9, 714–729. [Google Scholar]
  80. Pruszko, M.; Milano, E.; Forcato, M.; Donzelli, S.; Ganci, F.; Di Agostino, S.; De Panfilis, S.; Fazi, F.; Bates, D.O.; Bicciato, S.; et al. The mutant p53-ID4 complex controls VEGFA isoforms by recruiting lncRNA MALAT1. EMBO Rep. 2017, 18, 1331–1351. [Google Scholar] [CrossRef]
  81. Latorre, E.; Carelli, S.; Raimondi, I.; D’Agostino, V.; Castiglioni, I.; Zucal, C.; Moro, G.; Luciani, A.; Ghilardi, G.; Monti, E.; et al. The Ribonucleic Complex HuR-MALAT1 Represses CD133 Expression and Suppresses Epithelial-Mesenchymal Transition in Breast Cancer. Cancer Res. 2016, 76, 2626–2636. [Google Scholar] [CrossRef] [Green Version]
  82. Arun, G.; Diermeier, S.; Akerman, M.; Chang, K.-C.; Wilkinson, J.E.; Hearn, S.; Kim, Y.; MacLeod, A.R.; Krainer, A.R.; Norton, L.; et al. Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev. 2016, 30, 34–51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Kim, J.; Piao, H.L.; Kim, B.J.; Yao, F.; Han, Z.; Wang, Y.; Xiao, Z.; Siverly, A.N.; Lawhon, S.E.; Ton, B.N.; et al. Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat. Genet. 2018, 50, 1705–1715. [Google Scholar] [CrossRef] [PubMed]
  84. Zhang, H.-Y.; Liang, F.; Zhang, J.-W.; Wang, F.; Wang, L.; Kang, X.-G. Effects of long noncoding RNA-ROR on tamoxifen resistance of breast cancer cells by regulating microRNA-205. Cancer Chemother. Pharmacol. 2017, 79, 327–337. [Google Scholar] [CrossRef]
  85. Li, Y.; Jiang, B.; Zhu, H.; Qu, X.; Zhao, L.; Tan, Y.; Jiang, Y.; Liao, M.; Wu, X. Inhibition of long non-coding RNA ROR reverses resistance to Tamoxifen by inducing autophagy in breast cancer. Tumour Biol. 2017, 39, 1010428317705790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Peng, W.X.; Huang, J.G.; Yang, L.; Gong, A.H.; Mo, Y.Y. Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer. Mol. Cancer 2017, 16, 161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Loewer, S.; Cabili, M.N.; Guttman, M.; Loh, Y.H.; Thomas, K.; Park, I.H.; Garber, M.; Curran, M.; Onder, T.; Agarwal, S.; et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat. Genet. 2010, 42, 1113–1117. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Hou, L.; Tu, J.; Cheng, F.; Yang, H.; Yu, F.; Wang, M.; Liu, J.; Fan, J.; Zhou, G. Long noncoding RNA ROR promotes breast cancer by regulating the TGF-β pathway. Cancer Cell Int. 2018, 18, 142. [Google Scholar] [CrossRef] [Green Version]
  89. Eades, G.; Wolfson, B.; Zhang, Y.; Li, Q.; Yao, Y.; Zhou, Q. lincRNA-RoR and miR-145 Regulate Invasion in Triple-Negative Breast Cancer via Targeting ARF6. Mol. Cancer Res. 2015, 13, 330–338. [Google Scholar] [CrossRef] [Green Version]
  90. Ma, J.; Yang, Y.; Huo, D.; Wang, Z.; Zhai, X.; Chen, J.; Sun, H.; An, W.; Jie, J.; Yang, P. LincRNA-RoR/miR-145 promote invasion and metastasis in triple-negative breast cancer via targeting MUC1. Biochem. Biophys. Res. Commun. 2018, 500, 614–620. [Google Scholar] [CrossRef]
  91. Luo, C.; Cao, J.; Peng, R.; Guo, Q.; Ye, H.; Wang, P.; Wang, K.; Song, C. Functional Variants in Linc-ROR are Associated with mRNA Expression of Linc-ROR and Breast Cancer Susceptibility. Sci. Rep. 2018, 8, 4680. [Google Scholar] [CrossRef]
  92. Ma, T.; Liang, Y.; Li, Y.; Song, X.; Zhang, N.; Li, X.; Chen, B.; Zhao, W.; Wang, L.; Yang, Q. LncRNA LINP1 confers tamoxifen resistance and negatively regulated by ER signaling in breast cancer. Cell. Signal. 2020, 68, 109536. [Google Scholar] [CrossRef] [PubMed]
  93. Zhang, Y.; He, Q.; Hu, Z.; Feng, Y.; Fan, L.; Tang, Z.; Yuan, J.; Shan, W.; Li, C.; Hu, X.; et al. Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer. Nat. Struct. Mol. Biol. 2016, 23, 522–530. [Google Scholar] [CrossRef] [PubMed]
  94. Liang, Y.; Li, Y.; Song, X.; Zhang, N.; Sang, Y.; Zhang, H.; Liu, Y.; Chen, B.; Zhao, W.; Wang, L.; et al. Long noncoding RNA LINP1 acts as an oncogene and promotes chemoresistance in breast cancer. Cancer Biol. Ther. 2018, 19, 120–131. [Google Scholar] [CrossRef] [Green Version]
  95. Liu, Y.; Li, M.; Yu, H.; Piao, H. lncRNA CYTOR promotes tamoxifen resistance in breast cancer cells via sponging miR-125a-5p. Int. J. Mol. Med. 2020, 45, 497–509. [Google Scholar] [CrossRef] [Green Version]
  96. Van Grembergen, O.; Bizet, M.; de Bony, E.J.; Calonne, E.; Putmans, P.; Brohée, S.; Olsen, C.; Guo, M.; Bontempi, G.; Sotiriou, C.; et al. Portraying breast cancers with long noncoding RNAs. Sci. Adv. 2016, 2, e1600220. [Google Scholar] [CrossRef] [Green Version]
  97. Shen, X.; Zhong, J.; Yu, P.; Zhao, Q.; Huang, T. YY1-regulated LINC00152 promotes triple negative breast cancer progression by affecting on stability of PTEN protein. Biochem. Biophys. Res. Commun. 2019, 509, 448–454. [Google Scholar] [CrossRef]
  98. Ingle, J.N.; Xie, F.; Ellis, M.J.; Goss, P.E.; Shepherd, L.E.; Chapman, J.W.; Chen, B.E.; Kubo, M.; Furukawa, Y.; Momozawa, Y.; et al. Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy. Cancer Res. 2016, 76, 7012–7023. [Google Scholar] [CrossRef] [Green Version]
  99. Cairns, J.; Ingle, J.N.; Kalari, K.R.; Shepherd, L.E.; Kubo, M.; Goetz, M.P.; Weinshilboum, R.M.; Wang, L. The lncRNA MIR2052HG regulates ERα levels and aromatase inhibitor resistance through LMTK3 by recruiting EGR1. Breast Cancer Res. 2019, 21, 47. [Google Scholar] [CrossRef] [Green Version]
  100. Giamas, G.; Filipović, A.; Jacob, J.; Messier, W.; Zhang, H.; Yang, D.; Zhang, W.; Shifa, B.A.; Photiou, A.; Tralau-Stewart, C.; et al. Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer. Nat. Med. 2011, 17, 715–719. [Google Scholar] [CrossRef]
  101. Huang, S.; Chi, Y.; Chi, W.; Guo, R.; Su, Y.; Xue, J.; Zhou, S.; Wang, J.; Yang, Z.; Nie, J.; et al. LINC00309 is associated with short disease-free survival in breast cancer. Cancer Cell Int. 2019, 19, 210. [Google Scholar] [CrossRef]
  102. Gu, J.; Wang, Y.; Wang, X.; Zhou, D.; Shao, C.; Zhou, M.; He, Z. Downregulation of lncRNA GAS5 confers tamoxifen resistance by activating miR-222 in breast cancer. Cancer Lett. 2018, 434, 1–10. [Google Scholar] [CrossRef] [PubMed]
  103. Schneider, C.; King, R.M.; Philipson, L. Genes specifically expressed at growth arrest of mammalian cells. Cell 1988, 54, 787–793. [Google Scholar] [CrossRef]
  104. Goustin, A.S.; Thepsuwan, P.; Kosir, M.A.; Lipovich, L. The Growth-Arrest-Specific (GAS)-5 Long Non-Coding RNA: A Fascinating lncRNA Widely Expressed in Cancers. Non-Coding RNA 2019, 5, 46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Zhang, Z.; Zhu, Z.; Watabe, K.; Zhang, X.; Bai, C.; Xu, M.; Wu, F.; Mo, Y.Y. Negative regulation of lncRNA GAS5 by miR-21. Cell Death Differ. 2013, 20, 1558–1568. [Google Scholar] [CrossRef] [Green Version]
  106. Li, S.; Zhou, J.; Wang, Z.; Wang, P.; Gao, X.; Wang, Y. Long noncoding RNA GAS5 suppresses triple negative breast cancer progression through inhibition of proliferation and invasion by competitively binding miR-196a-5p. Biomed. Pharmacother. 2018, 104, 451–457. [Google Scholar] [CrossRef]
  107. Kino, T.; Hurt, D.E.; Ichijo, T.; Nader, N.; Chrousos, G.P. Noncoding RNA Gas5 Is a Growth Arrest- and Starvation-Associated Repressor of the Glucocorticoid Receptor. Sci. Signal. 2010, 3, ra8. [Google Scholar] [CrossRef] [Green Version]
  108. Hudson, W.H.; Pickard, M.R.; de Vera, I.M.; Kuiper, E.G.; Mourtada-Maarabouni, M.; Conn, G.L.; Kojetin, D.J.; Williams, G.T.; Ortlund, E.A. Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate. Nat. Commun. 2014, 5, 5395. [Google Scholar] [CrossRef] [Green Version]
  109. Tang, Y.; Wang, Y.; Wang, X.; Liu, Y.; Zheng, K. A Genetic Variant of rs145204276 in the Promoter Region of Long Noncoding RNA GAS5 Is Associated With a Reduced Risk of Breast Cancer. Clin. Breast Cancer 2019, 19, e415–e421. [Google Scholar] [CrossRef]
  110. Niknafs, Y.S.; Han, S.; Ma, T.; Speers, C.; Zhang, C.; Wilder-Romans, K.; Iyer, M.K.; Pitchiaya, S.; Malik, R.; Hosono, Y.; et al. The lncRNA landscape of breast cancer reveals a role for DSCAM-AS1 in breast cancer progression. Nat. Commun. 2016, 7, 12791. [Google Scholar] [CrossRef]
  111. Ma, Y.; Bu, D.; Long, J.; Chai, W.; Dong, J. LncRNA DSCAM-AS1 acts as a sponge of miR-137 to enhance Tamoxifen resistance in breast cancer. J. Cell. Physiol. 2019, 234, 2880–2894. [Google Scholar] [CrossRef]
  112. Miano, V.; Ferrero, G.; Reineri, S.; Caizzi, L.; Annaratone, L.; Ricci, L.; Cutrupi, S.; Castellano, I.; Cordero, F.; De Bortoli, M. Luminal long non-coding RNAs regulated by estrogen receptor alpha in a ligand-independent manner show functional roles in breast cancer. Oncotarget 2016, 7, 3201–3216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Sun, W.; Li, A.Q.; Zhou, P.; Jiang, Y.Z.; Jin, X.; Liu, Y.R.; Guo, Y.J.; Yang, W.T.; Shao, Z.M.; Xu, X.E. DSCAM-AS1 regulates the G1/S cell cycle transition and is an independent prognostic factor of poor survival in luminal breast cancer patients treated with endocrine therapy. Cancer Med. 2018, 7, 6137–6146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Liang, W.H.; Li, N.; Yuan, Z.Q.; Qian, X.L.; Wang, Z.H. DSCAM-AS1 promotes tumor growth of breast cancer by reducing miR-204-5p and up-regulating RRM2. Mol. Carcinog. 2019, 58, 461–473. [Google Scholar] [CrossRef] [PubMed]
  115. Tomita, S.; Abdalla, M.O.A.; Fujiwara, S.; Matsumori, H.; Maehara, K.; Ohkawa, Y.; Iwase, H.; Saitoh, N.; Nakao, M. A cluster of noncoding RNAs activates the ESR1 locus during breast cancer adaptation. Nat. Commun. 2015, 6, 6966. [Google Scholar] [CrossRef]
  116. Mansoori, Y.; Zendehbad, Z.; Askari, A.; Kouhpayeh, A.; Tavakkoly-Bazzaz, J.; Nariman-Saleh-Fam, Z.; Bastami, M.; Saadatian, Z.; Mansoori, B.; Yousefvand, A.; et al. Breast cancer-linked lncRNA u-Eleanor is upregulated in breast of healthy women with lack or short duration of breastfeeding. J. Cell. Biochem. 2019, 120, 9869–9876. [Google Scholar] [CrossRef]
  117. Bernstein, L. Epidemiology of endocrine-related risk factors for breast cancer. J. Mammary Gland Biol. Neoplasia 2002, 7, 3–15. [Google Scholar] [CrossRef]
  118. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 2002, 360, 187–195. [Google Scholar] [CrossRef]
  119. Zhou, Y.; Chen, J.; Li, Q.; Huang, W.; Lan, H.; Jiang, H. Association Between Breastfeeding and Breast Cancer Risk: Evidence from a Meta-analysis. Breastfeed. Med. 2015, 10, 175–182. [Google Scholar] [CrossRef]
  120. Abdalla, M.O.A.; Yamamoto, T.; Maehara, K.; Nogami, J.; Ohkawa, Y.; Miura, H.; Poonperm, R.; Hiratani, I.; Nakayama, H.; Nakao, M.; et al. The Eleanor ncRNAs activate the topological domain of the ESR1 locus to balance against apoptosis. Nat. Commun. 2019, 10, 3778. [Google Scholar] [CrossRef] [Green Version]
  121. Dixon, J.R.; Gorkin, D.U.; Ren, B. Chromatin Domains: The Unit of Chromosome Organization. Mol. Cell 2016, 62, 668–680. [Google Scholar] [CrossRef] [Green Version]
  122. Yamamoto, T.; Sakamoto, C.; Tachiwana, H.; Kumabe, M.; Matsui, T.; Yamashita, T.; Shinagawa, M.; Ochiai, K.; Saitoh, N.; Nakao, M. Endocrine therapy-resistant breast cancer model cells are inhibited by soybean glyceollin I through Eleanor non-coding RNA. Sci. Rep. 2018, 8, 15202. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Wang, K.; Li, J.; Xiong, Y.F.; Zeng, Z.; Zhang, X.; Li, H.Y. A Potential Prognostic Long Noncoding RNA Signature to Predict Recurrence among ER-positive Breast Cancer Patients Treated with Tamoxifen. Sci. Rep. 2018, 8, 3179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Levin, A.A. Treating Disease at the RNA Level with Oligonucleotides. N. Engl. J. Med. 2019, 380, 57–70. [Google Scholar] [CrossRef] [PubMed]
  125. Rigo, F.; Hua, Y.; Krainer, A.R.; Bennett, C.F. Antisense-based therapy for the treatment of spinal muscular atrophy. J. Cell Biol. 2012, 199, 21–25. [Google Scholar] [CrossRef]
  126. Finkel, R.S.; Mercuri, E.; Darras, B.T.; Connolly, A.M.; Kuntz, N.L.; Kirschner, J.; Chiriboga, C.A.; Saito, K.; Servais, L.; Tizzano, E.; et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N. Engl. J. Med. 2017, 377, 1723–1732. [Google Scholar] [CrossRef] [Green Version]
  127. Ajufo, E.; Rader, D.J. New Therapeutic Approaches for Familial Hypercholesterolemia. Annu. Rev. Med. 2018, 69, 113–131. [Google Scholar] [CrossRef]
  128. Agarwala, A.; Jones, P.; Nambi, V. The Role of Antisense Oligonucleotide Therapy in Patients with Familial Hypercholesterolemia: Risks, Benefits, and Management Recommendations. Curr. Atheroscler. Rep. 2015, 17, 467. [Google Scholar] [CrossRef]
  129. Chistiakov, D.A.; Myasoedova, V.A.; Grechko, A.V.; Melnichenko, A.A.; Orekhov, A.N. New biomarkers for diagnosis and prognosis of localized prostate cancer. Semin. Cancer Biol. 2018, 52, 9–16. [Google Scholar] [CrossRef]
Cancers 12 01424 g001 550
Figure 1. Classification of long noncoding RNAs (lncRNAs). Based on the positions of their loci on the genome, lncRNAs are classified into one or more of five categories: (A) sense, (B) antisense, (C) bidirectional, (D) intronic, and (E) intergenic.
Figure 1. Classification of long noncoding RNAs (lncRNAs). Based on the positions of their loci on the genome, lncRNAs are classified into one or more of five categories: (A) sense, (B) antisense, (C) bidirectional, (D) intronic, and (E) intergenic.
Cancers 12 01424 g001
Cancers 12 01424 g002 550
Figure 2. Schematic representation of the functions of HOTAIR, TMPO-AS1, and ADAMTS9-AS2 in the tamoxifen resistance of breast cancer. HOTAIR enhances tamoxifen resistance by regulating the expression and activity of ERα. TMPO-AS1 binds and stabilizes ESR1 mRNA to enhance tamoxifen resistance. On the other hand, ADAMTS9-AS2 downregulates tamoxifen resistance by competing with miR-130a-5p to increase PTEN expression. HOTAIR: HOX transcript antisense RNA; TMPO-AS1: thymopoietin antisense transcript 1; ADAMTS9-AS2: ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9) antisense RNA 2; ERα: estrogen receptor α; PTEN: phosphatase and tensin homolog.
Figure 2. Schematic representation of the functions of HOTAIR, TMPO-AS1, and ADAMTS9-AS2 in the tamoxifen resistance of breast cancer. HOTAIR enhances tamoxifen resistance by regulating the expression and activity of ERα. TMPO-AS1 binds and stabilizes ESR1 mRNA to enhance tamoxifen resistance. On the other hand, ADAMTS9-AS2 downregulates tamoxifen resistance by competing with miR-130a-5p to increase PTEN expression. HOTAIR: HOX transcript antisense RNA; TMPO-AS1: thymopoietin antisense transcript 1; ADAMTS9-AS2: ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9) antisense RNA 2; ERα: estrogen receptor α; PTEN: phosphatase and tensin homolog.
Cancers 12 01424 g002
Cancers 12 01424 g003 550
Figure 3. Schematic representation of the functions of UCA1, lincRNA-ROR, and lncRNA MIR2052HG in the tamoxifen resistance of breast cancer. (A) UCA1 promotes the tamoxifen resistance by several mechanisms. UCA1 activates mTOR, Wnt/β-catenin, and PI3K/AKT signaling pathways to enhance tamoxifen resistance. In addition, UCA1 binds to EZH2 and epigenetically suppresses p21 expression. Moreover, UCA1 sponges miR-18 to upregulate HIF1α expression. Since HIF1α induces UCA1 expression, UCA1 and HIF1α form a feedback regulatory loop to strengthen tamoxifen resistance. (B) LincRNA-ROR enhances tamoxifen resistance by inhibiting autophagy. Moreover, lincRNA-ROR induces the degradation of an ERK-specific phosphatase, DUSP7, resulting in ERα activation mediated by the MAPK/ERK signaling pathway. LincRNA-ROR also acts as a competing endogenous RNA (ceRNA), which sponges miR-205-5p to upregulate the expression of EMT-related genes ZEB1/2 and contributes to tamoxifen resistance. (C) MIR2052HG increases the expression of LMTK3. LMTK3 suppresses the activity of PKC, which increases the expression of ESR1 mRNA and ERα protein through the inactivation of AKT and MEK/ERK/RSK1 signaling pathway, respectively. UCA1: urothelial cancer associated 1; lincRNA-ROR: large intergenic noncoding RNA-regulator of reprogramming; MIR2052HG: miR2052 host gene; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; EZH2: enhancer of zeste homolog 2; HIF1α: hypoxia-inducible factor 1α; DUSP7: dual specificity phosphatase 7; MAPK/ERK: mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK); ZEB1/2: zinc finger E-box binding homeobox 1/2; LMTK3: lemur tyrosine kinase 3; PKC: protein kinase C; ESR1: estrogen receptor 1; MEK: MAPK/ERK kinase; RSK1: ribosomal S6 kinase 1.
Figure 3. Schematic representation of the functions of UCA1, lincRNA-ROR, and lncRNA MIR2052HG in the tamoxifen resistance of breast cancer. (A) UCA1 promotes the tamoxifen resistance by several mechanisms. UCA1 activates mTOR, Wnt/β-catenin, and PI3K/AKT signaling pathways to enhance tamoxifen resistance. In addition, UCA1 binds to EZH2 and epigenetically suppresses p21 expression. Moreover, UCA1 sponges miR-18 to upregulate HIF1α expression. Since HIF1α induces UCA1 expression, UCA1 and HIF1α form a feedback regulatory loop to strengthen tamoxifen resistance. (B) LincRNA-ROR enhances tamoxifen resistance by inhibiting autophagy. Moreover, lincRNA-ROR induces the degradation of an ERK-specific phosphatase, DUSP7, resulting in ERα activation mediated by the MAPK/ERK signaling pathway. LincRNA-ROR also acts as a competing endogenous RNA (ceRNA), which sponges miR-205-5p to upregulate the expression of EMT-related genes ZEB1/2 and contributes to tamoxifen resistance. (C) MIR2052HG increases the expression of LMTK3. LMTK3 suppresses the activity of PKC, which increases the expression of ESR1 mRNA and ERα protein through the inactivation of AKT and MEK/ERK/RSK1 signaling pathway, respectively. UCA1: urothelial cancer associated 1; lincRNA-ROR: large intergenic noncoding RNA-regulator of reprogramming; MIR2052HG: miR2052 host gene; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; EZH2: enhancer of zeste homolog 2; HIF1α: hypoxia-inducible factor 1α; DUSP7: dual specificity phosphatase 7; MAPK/ERK: mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK); ZEB1/2: zinc finger E-box binding homeobox 1/2; LMTK3: lemur tyrosine kinase 3; PKC: protein kinase C; ESR1: estrogen receptor 1; MEK: MAPK/ERK kinase; RSK1: ribosomal S6 kinase 1.
Cancers 12 01424 g003
Cancers 12 01424 g004 550
Figure 4. Schematic representation of the functions of GAS5, DSCAM-AS1, and Eleanors in the tamoxifen resistance of breast cancer. GAS5 sponges miR-222 and upregulates PTEN expression to enhance tamoxifen resistance. DSCAM-AS1 also sponges miR-137 to increase EPS8, which contributes to tamoxifen resistance. On the other hand, Eleanors promotes tamoxifen resistance by upregulating ESR1 expression. GAS5: growth-arrest specific 5; DSCAM-AS1: Down syndrome cell adhesion molecule antisense RNA 1; Eleanors: ESR1 locus enhancing and activating noncoding RNAs; PTEN: phosphatase and tensin homolog; EPS8: epidermal growth factor receptor pathway substrate 8.
Figure 4. Schematic representation of the functions of GAS5, DSCAM-AS1, and Eleanors in the tamoxifen resistance of breast cancer. GAS5 sponges miR-222 and upregulates PTEN expression to enhance tamoxifen resistance. DSCAM-AS1 also sponges miR-137 to increase EPS8, which contributes to tamoxifen resistance. On the other hand, Eleanors promotes tamoxifen resistance by upregulating ESR1 expression. GAS5: growth-arrest specific 5; DSCAM-AS1: Down syndrome cell adhesion molecule antisense RNA 1; Eleanors: ESR1 locus enhancing and activating noncoding RNAs; PTEN: phosphatase and tensin homolog; EPS8: epidermal growth factor receptor pathway substrate 8.
Cancers 12 01424 g004
Cancers 12 01424 g005 550
Figure 5. Antisense oligonucleotides (ASOs) in clinical use. (A) Nusinersen binds to a splicing regulatory sequence called intronic splicing silencer-N1 (ISS-N1) within intron 7 of SMN2 pre-mRNA, and enhances the inclusion of exon 7, resulting in the production of SMN2 mRNA coding the full-length SMN protein. (B) Mipomersen binds to ApoB-100 mRNA and causes its degradation, mediated by ribonuclease H (RNaseH). SMN2: survival of motor neuron 2: centromeric; SMN: survival of motor neuron; ApoB-100: apolipoprotein B-100.
Figure 5. Antisense oligonucleotides (ASOs) in clinical use. (A) Nusinersen binds to a splicing regulatory sequence called intronic splicing silencer-N1 (ISS-N1) within intron 7 of SMN2 pre-mRNA, and enhances the inclusion of exon 7, resulting in the production of SMN2 mRNA coding the full-length SMN protein. (B) Mipomersen binds to ApoB-100 mRNA and causes its degradation, mediated by ribonuclease H (RNaseH). SMN2: survival of motor neuron 2: centromeric; SMN: survival of motor neuron; ApoB-100: apolipoprotein B-100.
Cancers 12 01424 g005
Table
Table 1. LncRNAs regulating endocrine therapy resistance in breast cancer.
Table 1. LncRNAs regulating endocrine therapy resistance in breast cancer.
LncRNAsEffects on Endocrine Therapy ResistanceMolecular Mechanisms Regulating Endocrine Therapy ResistanceBreast Cancer Cells or Tissues Used for Analyzing the Mechanisms of LncRNAs
Antisense lncRNAs
HOTAIRUp-regulationUpregulating the activity of ERα under estrogen-starved condition [32]MCF7 and an MCF7-derived tamoxifen-resistant cell line (TamR MCF7) [32]
TMPO-AS1Up-regulationUpregulating ESR1 mRNA stability [41]MCF7, T47D, and MCF7-derived tamoxifen-resistant cells (OHTR cells), as well as MCF7 cultured under long-term estrogen-deprivation conditions (LTED cells) [41]
ADAMTS9-AS2Down-regulationInhibiting miR-130a-5p activity to increase the expression of PTEN [45]MCF7 and an MCF7-derived tamoxifen-resistant cell line (MCF-7R) [45]
PINK1-ASDown-regulation Possibly regulating several relapse or metastasis-related pathways, such as PI3K/AKT and Wnt signaling pathways [123]ER-positive breast tumors from patients who were primarily treated with tamoxifen as the unique endocrine therapy [123]
RP11-259N19.1Up-regulation
KLF3-AS1Down-regulation
PDCD4-AS1Down-regulation
PP14571Up-regulation
RP11-69E11.4Down-regulation
LincRNAs
UCA1Up-regulation
a)
Activating mTOR, Wnt/β-catenin, and PI3K/AKT signaling pathways [53,54,55];
b)
Promoting EZH2 mediated repression of p21 [55];
c)
Inhibiting miR-18a activity to increase HIF1α expression [56]
MCF7 and MCF7-derived tamoxifen- and ICI182,780-resistant cell lines (LCC2 and LCC9) [53];
MCF7, T47D, and tamoxifen-resistant cells derived from MCF7 and T47D (MCF-7-R and T47D-R) [54];
LCC2 [55], MCF7, BTB474, LCC2, and LCC9 [56]
BCAR4Up-regulationUpregulating tamoxifen resistance of ZR-75-1 and ICI182,780 resistance of MCF7 in a HER2/ErbB2-, ErbB3-, and ErbB4-dependent manner [58,59,60,61]ZR-75-1 [58,59,60], MCF7 [61]
MALAT1Up-regulation [62]Unknown
LincRNA-RORUp-regulation
a)
Inhibiting autophagy [85];
b)
Promoting ligand-independent activation of ERα and estrogen-independent growth [86];
c)
Inhibiting miR-205-5p activity to increase the expression of ZEB1/2 [84]
BT474 [85]
MCF7 [86]
MCF7, an MCF7-derived tamoxifen-resistant cell line (MCF7/TR5), and MDA-MB-231 [84]
LINP1Up-regulationDecreasing ERα expression level [92]MCF7, T47D, tamoxifen-resistant cells derived from MCF7 and T47D (MCF-7/TAMR and T47D/TAMR) [92]
CYTORUp-regulationInhibiting miR-125a-5p to increase the expression of SRF [95]MCF7-derived tamoxifen-resistant cell lines (MCF7/TAM1 and MCF7/TAM2) [95]
MIR2052HGUp-regulationIncreasing the expression of LMTK3 to upregulate ERα expression [99]CAMA-1, an MCF7 cell line stably transfected CYP19A1 (MCF7/AC1), and an anastrozole-resistant MCF7 cell line (MCF7/AnaR) [99]
LINC00309Up-regulation [100]Unknown
LINC00339Down-regulationPossibly regulating several relapse or metastasis-related pathways, such as PI3K/AKT and Wnt signaling pathways [123]ER-positive breast tumors from patients who were primarily treated with tamoxifen as the unique endocrine therapy [123]
LINC00472Down-regulation
RP11-351I21.11Down-regulation
KB-1460A1.5Up-regulation
Other lncRNAs
GAS5Down-regulationInhibiting miR-222 activity to increase the expression of PTEN [102]MCF-derived, tamoxifen-resistant cell line (MCF-7R) [102]
DSCAM-AS1Up-regulationInhibiting miR-137 to increase EPS8 [111]MCF7-derived, tamoxifen-resistant cells (TR MCF7) [111]
EleanorsUp-regulationIncreasing the expression of ESR1 [115.120]MCF7 and MCF7 cultured under long-term estrogen-deprivation conditions (LTED cells) [115,120]
PKD1P6-NPIPP1Down-regulationPossibly regulating several relapse or metastasis-related pathways, such as PI3K/AKT and Wnt signaling pathways [123]ER-positive breast tumors from patients who were primarily treated with tamoxifen as the unique endocrine therapy [123]

Share and Cite

MDPI and ACS Style

Takeiwa, T.; Ikeda, K.; Mitobe, Y.; Horie-Inoue, K.; Inoue, S. Long Noncoding RNAs Involved in the Endocrine Therapy Resistance of Breast Cancer. Cancers 2020, 12, 1424. https://doi.org/10.3390/cancers12061424

AMA Style

Takeiwa T, Ikeda K, Mitobe Y, Horie-Inoue K, Inoue S. Long Noncoding RNAs Involved in the Endocrine Therapy Resistance of Breast Cancer. Cancers. 2020; 12(6):1424. https://doi.org/10.3390/cancers12061424

Chicago/Turabian Style

Takeiwa, Toshihiko, Kazuhiro Ikeda, Yuichi Mitobe, Kuniko Horie-Inoue, and Satoshi Inoue. 2020. "Long Noncoding RNAs Involved in the Endocrine Therapy Resistance of Breast Cancer" Cancers 12, no. 6: 1424. https://doi.org/10.3390/cancers12061424

APA Style

Takeiwa, T., Ikeda, K., Mitobe, Y., Horie-Inoue, K., & Inoue, S. (2020). Long Noncoding RNAs Involved in the Endocrine Therapy Resistance of Breast Cancer. Cancers, 12(6), 1424. https://doi.org/10.3390/cancers12061424

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop