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Molecular Mechanisms of Breast Cancer: Toward Advanced Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (28 April 2024) | Viewed by 8874

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Special Issue Editors

Dr. Masa-Aki Shibata

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Guest Editor

Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki 569-8686, Osaka, Japan
Interests: mammary cancer; metastasis; inhibition; lymphangiogenesis; premetastatic niche; mouse
Special Issues, Collections and Topics in MDPI journals

Dr. Sasagu Kurozumi

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Guest Editor

Department of Breast Surgery, International University of Health and Walfare, Narita 286-8686, Chiba, Japan
Interests: breast cancer; artificial intelligence; biomarker research; pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast cancer is the most common cancer in women worldwide. Although advances in diagnosis and therapy have resulted in flat or declining mortality rates, the death rates remain high among women worldwide. In recent years, investigations in the biology of breast cancer have led to the determination of therapeutic strategies (e.g., hormonal therapy) based on histology and biomarkers (estrogen receptor, progesterone receptor, HER2). In particular, with the recent development of the molecular biology of cancer, devices using advanced technologies have appeared, which allow us to analyze the genome using circulating tumor cells in the blood, microRNAs in exosomes, and the composition of immune cells in tumors. In the future, the emergence of molecularly targeted drugs and immune checkpoint inhibitors will lead to a trend towards precision medicine to identify effective anti-tumor drugs, which will in turn lead to new therapeutic approaches. The scope of this Special Issue is to deepen our understanding of the molecular biology in breast cancer, and we hope to disseminate information on the latest findings and idea of advanced therapies, leading to the discovery of new molecular diagnostic techniques and targeted therapeutics.

Topics related to breast cancer in this Special Issue include, but are not limited to, the following:

Molecular tumor biology: signaling pathway, angiogenesis, lymphangiogenesis, apoptosis, autophagy, cell cycle, etc.
Tumor microenvironment: premetastatic niche and tumor immunology.
Cancer biomarkers: microRNAs, exosomes, screening and diagnosis.
Cancer therapy: target discovery, drug design, resistance, targeted therapy and precision medicine.
Molecular tumor pathology.
Animal experiment models.
Cancer epidemiology and prevention.
Metastasis inhibition.

Dr. Masa-Aki Shibata
Dr. Sasagu Kurozumi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

molecular tumor biology
tumor immunology
tumor microenvironment
premetastatic niche
cancer biomarkers
microRNAs
exosomes
cancer therapy
cancer epidemiology and prevention
metastasis inhibition
cancer stem cell

Published Papers (7 papers)

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Research

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26 pages, 4148 KiB

Open AccessArticle

Generation and Characterization of Trastuzumab/Pertuzumab-Resistant HER2-Positive Breast Cancer Cell Lines

by Marta Sanz-Álvarez, Melani Luque, Miriam Morales-Gallego, Ion Cristóbal, Natalia Ramírez-Merino, Yamileth Rangel, Yann Izarzugaza, Pilar Eroles, Joan Albanell, Juan Madoz-Gúrpide and Federico Rojo

Int. J. Mol. Sci. 2024, 25(1), 207; https://doi.org/10.3390/ijms25010207 - 22 Dec 2023

Cited by 1 | Viewed by 1097

Abstract

The combination of trastuzumab and pertuzumab as first-line therapy in patients with HER2-positive breast cancer has shown significant clinical benefits compared to trastuzumab alone. However, despite initial therapeutic success, most patients eventually progress, and tumors develop acquired resistance and invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance in order to develop targeted therapeutic strategies with improved efficacy. We generated four novel HER2-positive cell lines via prolonged exposure to trastuzumab and pertuzumab and determined their resistance rates. Long-term resistance was confirmed by a significant increase in the colony-forming capacity of the derived cells. We authenticated the molecular identity of the new lines via both immunohistochemistry for the clinical phenotype and molecular profiling of point mutations. HER2 overexpression was confirmed in all resistant cell lines, and acquisition of resistance to trastuzumab and pertuzumab did not translate into differences in ER, PR, and HER2 receptor expression. In contrast, changes in the expression and activity of other HER family members, particularly HER4, were observed. In the same vein, analyses of the receptor and effector kinase status of different cellular pathways revealed that the MAPK pathway may be involved in the acquisition of resistance to trastuzumab and pertuzumab. Finally, proteomic analysis confirmed a significant change in the abundance patterns of more than 600 proteins with implications in key biological processes, such as ribosome formation, mitochondrial activity, and metabolism, which could be relevant mechanisms in the generation of resistance in HER2-positive breast cancer. We concluded that these resistant BCCLs may be a valuable tool to better understand the mechanisms of acquisition of resistance to trastuzumab and pertuzumab-based anti-HER2 therapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Breast Cancer: Toward Advanced Therapy)

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11 pages, 4687 KiB

Open AccessArticle

Identification of MicroRNAs Associated with Histological Grade in Early-Stage Invasive Breast Cancer

by Sasagu Kurozumi, Naohiko Seki, Eriko Narusawa, Chikako Honda, Shoko Tokuda, Yuko Nakazawa, Takehiko Yokobori, Ayaka Katayama, Nigel P. Mongan, Emad A. Rakha, Tetsunari Oyama, Takaaki Fujii, Ken Shirabe and Jun Horiguchi

Int. J. Mol. Sci. 2024, 25(1), 35; https://doi.org/10.3390/ijms25010035 - 19 Dec 2023

Cited by 1 | Viewed by 1316

Abstract

This study aimed to identify microRNAs associated with histological grade using comprehensive microRNA analysis data obtained by next-generation sequencing from early-stage invasive breast cancer. RNA-seq data from normal breast and breast cancer samples were compared to identify candidate microRNAs with differential expression using bioinformatics. A total of 108 microRNAs were significantly differentially expressed in normal breast and breast cancer tissues. Using clinicopathological information and microRNA sequencing data of 430 patients with breast cancer from The Cancer Genome Atlas (TCGA), the differences in candidate microRNAs between low- and high-grade tumors were identified. Comparing the expression of the 108 microRNAs between low- and high-grade cases, 25 and 18 microRNAs were significantly upregulated and downregulated, respectively, in high-grade cases. Clustering analysis of the TCGA cohort using these 43 microRNAs identified two groups strongly predictive of histological grade. miR-3677 is a microRNA upregulated in high-grade breast cancer. The outcome analysis revealed that patients with high miR-3677 expression had significantly worse prognosis than those with low miR-3677 expression. This study shows that microRNAs are associated with histological grade in early-stage invasive breast cancer. These findings contribute to the elucidation of a new mechanism of breast cancer growth regulated by specific microRNAs. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Breast Cancer: Toward Advanced Therapy)

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18 pages, 6181 KiB

Open AccessArticle

PSPC1 Inhibition Synergizes with Poly(ADP-ribose) Polymerase Inhibitors in a Preclinical Model of BRCA-Mutated Breast/Ovarian Cancer

by Mithun Ghosh, Min Sil Kang, Nar Bahadur Katuwal, Sa Deok Hong, Yeong Gyu Jeong, Seong Min Park, Seul-Gi Kim and Yong Wha Moon

Int. J. Mol. Sci. 2023, 24(23), 17086; https://doi.org/10.3390/ijms242317086 - 03 Dec 2023

Viewed by 1457

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against BRCA1/2-mutated cancers through synthetic lethality. Unfortunately, most cases ultimately develop acquired resistance. Therefore, enhancing PARP inhibitor sensitivity and preventing resistance in those cells are an unmet clinical need. Here, we investigated the ability of paraspeckle component 1 (PSPC1), as an additional synthetic lethal partner with BRCA1/2, to enhance olaparib sensitivity in preclinical models of BRCA1/2-mutated breast and ovarian cancers. In vitro, the combined olaparib and PSPC1 small interfering RNA (siRNA) exhibited synergistic anti-proliferative activity in BRCA1/2-mutated breast and ovarian cancer cells. The combination therapy also demonstrated synergistic tumor inhibition in a xenograft mouse model. Mechanistically, olaparib monotherapy increased the expressions of p-ATM and DNA-PKcs, suggesting the activation of a DNA repair pathway, whereas combining PSPC1 siRNA with olaparib decreased the expressions of p-ATM and DNA-PKcs again. As such, the combination increased the formation of γH2AX foci, indicating stronger DNA double-strand breaks. Subsequently, these DNA-damaged cells escaped G2/M checkpoint activation, as indicated by the suppression of p-cdc25C (Ser216) and p-cdc2 (Tyr15) after combination treatment. Finally, these cells entered mitosis, which induced increased apoptosis. Thus, this proves that PSPC1 inhibition enhances olaparib sensitivity by targeting DNA damage response in our preclinical model. The combination of olaparib and PSPC1 inhibition merits further clinical investigation to enhance PARP inhibitor efficacy. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Breast Cancer: Toward Advanced Therapy)

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18 pages, 3615 KiB

Open AccessArticle

Fyn-Mediated Paxillin Tyrosine 31 Phosphorylation Regulates Migration and Invasion of Breast Cancer Cells

by Ying Zhang, Huanyu Zheng, Ming Xu, Noriko Maeda, Ryouichi Tsunedomi, Hiroko Kishi, Hiroaki Nagano and Sei Kobayashi

Int. J. Mol. Sci. 2023, 24(21), 15980; https://doi.org/10.3390/ijms242115980 - 05 Nov 2023

Cited by 1 | Viewed by 945

Abstract

Metastasis is the leading cause of death in breast cancer patients due to the lack of effective therapies. Elevated levels of paxillin expression have been observed in various cancer types, with tyrosine phosphorylation shown to play a critical role in driving cancer cell migration. However, the specific impact of the distinct tyrosine phosphorylation events of paxillin in the progression of breast cancer remains to be fully elucidated. Here, we found that paxillin overexpression in breast cancer tissue is associated with a patient’s poor prognosis. Paxillin knockdown inhibited the migration and invasion of breast cancer cells. Furthermore, the phosphorylation of paxillin tyrosine residue 31 (Tyr31) was significantly increased upon the TGF-β1-induced migration and invasion of breast cancer cells. Inhibiting Fyn activity or silencing Fyn decreases paxillin Tyr31 phosphorylation. The wild-type and constitutively active Fyn directly phosphorylate paxillin Tyr31 in an in vitro system, indicating that Fyn directly phosphorylates paxillin Tyr31. Additionally, the non-phosphorylatable mutant of paxillin at Tyr31 reduces actin stress fiber formation, migration, and invasion of breast cancer cells. Taken together, our results provide direct evidence that Fyn-mediated paxillin Tyr31 phosphorylation is required for breast cancer migration and invasion, suggesting that targeting paxillin Tyr31 phosphorylation could be a potential therapeutic strategy for mitigating breast cancer metastasis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Breast Cancer: Toward Advanced Therapy)

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16 pages, 3764 KiB

Open AccessArticle

ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling

by Shao-Ying Yang, Li Liao, Shu-Yuan Hu, Ling Deng, Lisa Andriani, Tai-Mei Zhang, Yin-Ling Zhang, Xiao-Yan Ma, Fang-Lin Zhang, Ying-Ying Liu and Da-Qiang Li

Int. J. Mol. Sci. 2023, 24(19), 14566; https://doi.org/10.3390/ijms241914566 - 26 Sep 2023

Cited by 1 | Viewed by 1069

Abstract

Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2α and enhanced its phosphorylation by promoting the interaction between eIF2α and GCN2. Phosphorylated eIF2α in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2α phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 has a functional and mechanistic role in TNBC metastasis and offers a new therapeutic strategy for targeting ETHE1-propelled TNBC using ISRIB. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Breast Cancer: Toward Advanced Therapy)

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13 pages, 4604 KiB

Open AccessArticle

BRD4 Inhibition Enhances the Antitumor Effects of Radiation Therapy in a Murine Breast Cancer Model

by Seongmin Kim, Seung Hyuck Jeon, Min Guk Han, Mi Hyun Kang and In Ah Kim

Int. J. Mol. Sci. 2023, 24(17), 13062; https://doi.org/10.3390/ijms241713062 - 22 Aug 2023

Cited by 1 | Viewed by 1310

Abstract

Bromodomain-containing protein 4 (BRD4) is an intracellular protein that regulates expression of various cellular functions. This study investigated whether BRD4 inhibition can alter the immunomodulatory and antitumor effects of radiation therapy (RT). A murine breast cancer cell line was implanted into BALB/c mice. The dual-tumor model was used to evaluate the abscopal effects of RT. A total of 24 Gy was delivered and BRD4 inhibitor was injected intravenously. Tumor size was measured, and in vivo imaging was performed to evaluate tumor growth. Flow cytometry and immunohistochemistry were performed to examine immunologic changes upon treatment. The combination of BRD4 inhibitor and RT significantly suppressed tumor growth compared to RT alone. BRD4 inhibitor reduced the size of the unirradiated tumor, indicating that it may induce systemic immune responses. The expression of HIF-1α and PD-L1 in the tumor was significantly downregulated by the BRD4 inhibitor. The proportion of M1 tumor-associated macrophages (TAMs) increased, and the proportion of M2 TAMs decreased upon BRD4 inhibition. BRD4 inhibitor expanded CD4⁺ and CD8⁺ T cell populations in the tumor microenvironment. Additionally, splenic monocytic myeloid derived suppressor cells, which were increased by RT, were reduced upon the addition of BRD4 inhibitor. Therefore, the addition of BRD4 inhibitor significantly enhanced the systemic antitumor responses of local RT. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Breast Cancer: Toward Advanced Therapy)

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Review

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21 pages, 2211 KiB

Open AccessReview

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

by Masayuki Nagahashi and Yasuo Miyoshi

Int. J. Mol. Sci. 2024, 25(6), 3354; https://doi.org/10.3390/ijms25063354 - 15 Mar 2024

Viewed by 881

Abstract

In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Breast Cancer: Toward Advanced Therapy)

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