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Molecular Biology of Breast Cancer

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

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 16368

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Dr. Maria Alexandra Brito

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Guest Editor

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
Interests: angiogenesis; blood–brain barrier; blood–tumor barrier; brain cancer treatment; brain metastasis; breast cancer; intercellular communication; glioma; tumor microenvironment; tumor heterogeneity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast cancer is the most common cancer in women, frequently developing metastases that are responsible for 90% of all breast cancer deaths.

This Special Issue intends to gather forefront knowledge about breast cancer, including signaling pathways involved in malignant cell survival, proliferation, invasion, and metastases development. It also encompasses the tumor microenvironment and the immune ecosystem, direct and vesicle-mediated intercellular communication, the regulatory role of microRNAs in tumorigenesis, and inter- and intra-tumoral heterogeneity. It also expects to emphasize the relevance of neovascularization and vascular co-option, as well as the blood–tumor barrier. Furthermore, it aims to highlight novel therapeutic strategies that can circumvent immune and therapeutic resistance and specifically target malignant cells, as well as innovative study and imaging tools. Contributions on these topics are welcome, including original research and reviews.

By bringing together state-of-the-art concepts on relevant topics, this Special Issue shall contribute to a better understanding of breast cancer molecular biology and diversity, which is essential for identifying targets and developing novel and personalized therapeutics to improve life quality and expectancy.

Dr. Maria Alexandra Brito
Guest Editor

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

breast cancer
immune cells
intercellular communication
metastases
microRNAs
extracellular vesicles
neovascularization
signaling pathways
therapeutics
tumor microenvironment

Published Papers (10 papers)

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Research

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17 pages, 4322 KiB

Open AccessArticle

EGR1 Regulation of Vasculogenic Mimicry in the MDA-MB-231 Triple-Negative Breast Cancer Cell Line through the Upregulation of KLF4 Expression

by Euitaek Jung, Young Han Lee, Sukjin Ou, Tae Yoon Kim and Soon Young Shin

Int. J. Mol. Sci. 2023, 24(18), 14375; https://doi.org/10.3390/ijms241814375 - 21 Sep 2023

Viewed by 1152

Abstract

Vasculogenic mimicry (VM) is an intriguing phenomenon observed in tumor masses, in which cancer cells organize themselves into capillary-like channels that closely resemble the structure and function of blood vessels. Although VM is believed to contribute to alternative tumor vascularization, the detailed regulatory mechanisms controlling these cellular processes remain poorly understood. Our study aimed to investigate the role of Early Growth Response 1 (EGR1) in regulating VM in aggressive cancer cells, specifically MDA-MB-231 triple-negative breast cancer cells. Our study revealed that EGR1 promotes the formation of capillary-like tubes by MDA-MB-231 cells in a 3-dimensional Matrigel matrix. EGR1 was observed to upregulate Kruppel-like factor 4 (KLF4) expression, which regulates the formation of the capillary-like tube structure. Additionally, our findings highlight the involvement of the ERK1/2 and p38 mitogen-activated protein kinase pathways in mediating the expression of EGR1 and KLF4, underscoring their crucial role in VM in MDA-MB-231 cells. Understanding these regulatory mechanisms will provide valuable insights into potential therapeutic targets for preventing VM during the treatment of triple-negative breast cancer. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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18 pages, 3021 KiB

Open AccessArticle

MEF2C and miR-194-5p: New Players in Triple Negative Breast Cancer Tumorigenesis

by Sara Caetano, Ana Rita Garcia, Inês Figueira and Maria Alexandra Brito

Int. J. Mol. Sci. 2023, 24(18), 14297; https://doi.org/10.3390/ijms241814297 - 19 Sep 2023

Cited by 2 | Viewed by 994

Abstract

Among breast cancer (BC) subtypes, the most aggressive is triple negative BC (TNBC), which is prone to metastasis. We previously found that microRNA (miR)-194-5p is downregulated at the early stages of TNBC brain metastasis development. Additionally, the transcription factor myocyte enhancer factor 2 (MEF2)C, a bioinformatically predicted miR-194-5p target, was increasingly expressed throughout TNBC brain metastasis formation and disease severity. However, the contributions of these two players to malignant cells’ features remain undetermined. This study aimed at disclosing the role of miR-194-5p and MEF2C in TNBC tumorigenesis. The transfection of 4T1 cells with a silencer for MEF2C or with a pre-miRNA for miR-194-5p was employed to study TNBC cells’ phenotypic alterations regarding epithelial and mesenchymal markers, as well as migratory capability alterations. MEF2C-silenced cells presented a decline in both vimentin and cytokeratin expression, whereas the overexpression of miR-194-5p promoted an increase in cytokeratin and a reduction in vimentin, reflecting the acquisition of an epithelial phenotype. Both treatments reduced TNBC cells’ migration. These results suggest that MEF2C may determine TNBC cells’ invasive properties by partially determining the occurrence of epithelial–mesenchymal transition, while the overexpression of miR-194-5p promotes a decline in TNBC cells’ aggressive behavior and reinforces this miRNA’s role as a tumor suppressor in TNBC. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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16 pages, 4876 KiB

Open AccessArticle

The Role of ARHGAP1 in Rho GTPase Inactivation during Metastasizing of Breast Cancer Cell Line MCF-7 after Treatment with Doxorubicin

by Imrich Géci, Peter Bober, Eva Filová, Evžen Amler and Ján Sabo

Int. J. Mol. Sci. 2023, 24(14), 11352; https://doi.org/10.3390/ijms241411352 - 12 Jul 2023

Cited by 1 | Viewed by 1556

Abstract

Breast cancer is the most prevalent cancer type in women worldwide. It proliferates rapidly and can metastasize into farther tissues at any stage due to the gradual invasiveness and motility of the tumor cells. These crucial properties are the outcome of the weakened intercellular adhesion, regulated by small guanosine triphosphatases (GTPases), which hydrolyze to the guanosine diphosphate (GDP)-bound conformation. We investigated the inactivating effect of ARHGAP1 on Rho GTPases involved signaling pathways after treatment with a high dose of doxorubicin. Label-free quantitative proteomic analysis of the proteome isolated from the MCF-7 breast cancer cell line, treated with 1 μM of doxorubicin, identified RAC1, CDC42, and RHOA GTPases that were inactivated by the ARHGAP1 protein. Upregulation of the GTPases involved in the transforming growth factor-beta (TGF-beta) signaling pathway initiated epithelial–mesenchymal transitions. These findings demonstrate a key role of the ARHGAP1 protein in the disruption of the cell adhesion and simultaneously allow for a better understanding of the molecular mechanism of the reduced cell adhesion leading to the subsequent metastasis. The conclusions of this study corroborate the hypothesis that chemotherapy with doxorubicin may increase the risk of metastases in drug-resistant breast cancer cells. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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17 pages, 2201 KiB

Open AccessArticle

Tamoxifen Modulates the Immune Landscape of the Tumour Microenvironment: The Paired Siglec-5/14 Checkpoint in Anti-Tumour Immunity in an In Vitro Model of Breast Cancer

by Przemyslaw Wielgat, Karol Rogowski, Robert Czarnomysy, Natalia Wawrusiewicz-Kurylonek, Karolina Narejko, Krzysztof Bielawski and Halina Car

Int. J. Mol. Sci. 2023, 24(6), 5512; https://doi.org/10.3390/ijms24065512 - 14 Mar 2023

Cited by 3 | Viewed by 1510

Abstract

Since the role of sialome–Siglec axis has been described as a regulatory checkpoint of immune homeostasis, the promotion of stimulatory or inhibitory Siglec-related mechanisms is crucial in cancer progression and therapy. Here, we investigated the effect of tamoxifen on the sialic acid–Siglec interplay and its significance in immune conversion in breast cancer. To mimic the tumour microenvironment, we used oestrogen-dependent or oestrogen-independent breast cancer cells/THP-1 monocytes transwell co-cultures exposed to tamoxifen and/or β-estradiol. We found changes in the cytokine profiles accompanied by immune phenotype switching, as measured by the expression of arginase-1. The immunomodulatory effects of tamoxifen in THP-1 cells occurred with the altered SIGLEC5 and SIGLEC14 genes and the expression of their products, as confirmed by RT-PCR and flow cytometry. Additionally, exposure to tamoxifen increased the binding of Siglec-5 and Siglec-14 fusion proteins to breast cancer cells; however, these effects appeared to be unassociated with oestrogen dependency. Our results suggest that tamoxifen-induced alterations in the immune activity of breast cancer reflect a crosstalk between the Siglec-expressing cells and the tumour’s sialome. Given the distribution of Siglec-5/14, the expression profile of inhibitory and activatory Siglecs in breast cancer patients may be useful in the verification of therapeutic strategies and predicting the tumour’s behaviour and the patient’s overall survival. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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16 pages, 4551 KiB

Open AccessArticle

Transcriptomic Profile of Canine Mammary Ductal Carcinoma

by Driéle B. Santos, Geysson J. Fernandez, Luciana M. C. Pardini, Maria Inês M. C. Pardini and Adriana C. Ferrasi

Int. J. Mol. Sci. 2023, 24(6), 5212; https://doi.org/10.3390/ijms24065212 - 8 Mar 2023

Cited by 2 | Viewed by 1568

Abstract

Dogs can be excellent models for spontaneous studies about breast cancers, presenting similarities in clinical behavior and molecular pathways of the disease. Thus, analyses of the canine transcriptome can identify deregulated genes and pathways, contributing to the identification of biomarkers and new therapeutic targets, benefiting humans and animals. In this context, this study aimed to determine the transcriptional profile of canine mammary ductal carcinoma and contribute to the clarification of the importance of deregulated molecules in the molecular pathways involved in the disease. Therefore, we used mammary ductal carcinoma tissue samples and non-tumor mammary tissue from the radical mastectomy of six female dogs. Sequencing was performed on the NextSeq-500 System platform. A comparison of carcinoma tissue and normal tissue revealed 633 downregulated and 573 upregulated genes, which were able to differentiate the groups by principal component analysis. Gene ontology analysis indicated that inflammatory, cell differentiation and adhesion, and extracellular matrix maintenance pathways were mainly deregulated in this series. The main differentially expressed genes observed in this research can indicate greater disease aggressiveness and worse prognosis. Finally, the study of the canine transcriptome indicates that it is an excellent model to generate information relevant to oncology in both species. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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18 pages, 1550 KiB

Open AccessArticle

Association of the Telomerase Reverse Transcriptase rs10069690 Polymorphism with the Risk, Age at Onset and Prognosis of Triple Negative Breast Cancer

by Karin Zins, Elisabeth Peka, Heidi Miedl, Stefanie Ecker, Dietmar Abraham and Martin Schreiber

Int. J. Mol. Sci. 2023, 24(3), 1825; https://doi.org/10.3390/ijms24031825 - 17 Jan 2023

Cited by 3 | Viewed by 1466

Abstract

Telomerase reverse transcriptase (TERT) plays a key role in the maintenance of telomere DNA length. The rs10069690 single nucleotide variant, located in intron 4 of TERT, was found to be associated with telomere length and the risk of estrogen receptor-negative but not–positive breast cancer. This study aimed at analysis of the association of rs10069690 genotype and TERT expression with the risk, age at onset, prognosis, and clinically and molecularly relevant subtypes of breast cancer. Accordingly, rs10069690 was genotyped in a hospital-based case-control study of 403 female breast cancer patients and 246 female controls of a Central European (Austrian) study population, and the mRNA levels of TERT were quantified in 106 primary breast tumors using qRT-PCR. We found that in triple-negative breast cancer patients, the minor rs10069690 TT genotype tended to be associated with an increased breast cancer risk (OR, 1.87; 95% CI, 0.75–4.71; p = 0.155) and was significantly associated with 11.7 years younger age at breast cancer onset (p = 0.0002), whereas the CC genotype was associated with a poor brain metastasis-free survival (p = 0.009). Overall, our data show that the rs10069690 CC genotype and a high TERT expression tended to be associated with each other and with a poor prognosis. Our findings indicate a key role of rs10069690 in triple-negative breast cancer. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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15 pages, 2637 KiB

Open AccessArticle

Kalkitoxin: A Potent Suppressor of Distant Breast Cancer Metastasis

by Saroj Kumar Shrestha, Kyung Hyun Min, Se Woong Kim, Hyoungsu Kim, William H. Gerwick and Yunjo Soh

Int. J. Mol. Sci. 2023, 24(2), 1207; https://doi.org/10.3390/ijms24021207 - 7 Jan 2023

Cited by 1 | Viewed by 2325

Abstract

Bone metastasis resulting from advanced breast cancer causes osteolysis and increases mortality in patients. Kalkitoxin (KT), a lipopeptide toxin derived from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), has an anti-metastatic effect on cancer cells. We verified that KT suppressed cancer cell migration and invasion in vitro and in animal models in the present study. We confirmed that KT suppressed osteoclast-soup-derived MDA-MB-231 cell invasion in vitro and induced osteolysis in a mouse model, possibly enhancing/inhibiting metastasis markers. Furthermore, KT inhibits CXCL5 and CXCR2 expression, suppressing the secondary growth of breast cancer cells on the bone, brain, and lungs. The breast-cancer-induced osteolysis in the mouse model further reveals that KT plays a protective role, judging by micro-computed tomography and immunohistochemistry. We report for the first time the novel suppressive effects of KT on cancer cell migration and invasion in vitro and on MDA-MB-231-induced bone loss in vivo. These results suggest that KT may be a potential therapeutic drug for the treatment of breast cancer metastasis. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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14 pages, 1701 KiB

Open AccessArticle

Analysis of Intrinsic Breast Cancer Subtypes: The Clinical Utility of Epigenetic Biomarkers and TP53 Mutation Status in Triple-Negative Cases

by Ieva Sadzeviciene, Kristina Snipaitiene, Asta Scesnaite-Jerdiakova, Kristina Daniunaite, Rasa Sabaliauskaite, Aida Laurinaviciene, Monika Drobniene, Valerijus Ostapenko and Sonata Jarmalaite

Int. J. Mol. Sci. 2022, 23(23), 15429; https://doi.org/10.3390/ijms232315429 - 6 Dec 2022

Cited by 1 | Viewed by 1661

Abstract

This study aimed at analyzing the DNA methylation pattern and TP53 mutation status of intrinsic breast cancer (BC) subtypes for improved characterization and survival prediction. DNA methylation of 17 genes was tested by methylation-specific PCR in 116 non-familial BRCA mutation-negative BC and 29 control noncancerous cases. At least one gene methylation was detected in all BC specimens and a 10-gene panel statistically significantly separated tumors from noncancerous breast tissues. Methylation of FILIP1L and MT1E was predominant in triple-negative (TN) BC, while other BC subtypes were characterized by RASSF1, PRKCB, MT1G, APC, and RUNX3 hypermethylation. TP53 mutation (TP53-mut) was found in 38% of sequenced samples and mainly affected TN BC cases (87%). Cox analysis revealed that TN status, age at diagnosis, and RUNX3 methylation are independent prognostic factors for overall survival (OS) in BC. The combinations of methylated biomarkers, RUNX3 with MT1E or FILIP1L, were also predictive for shorter OS, whereas methylated FILIP1L was predictive of a poor outcome in the TP53-mut subgroup. Therefore, DNA methylation patterns of specific genes significantly separate BC from noncancerous breast tissues and distinguishes TN cases from non-TN BC, whereas the combination of two-to-three epigenetic biomarkers can be an informative tool for BC outcome predictions. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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Review

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29 pages, 1113 KiB

Open AccessReview

Microbial Therapy and Breast Cancer Management: Exploring Mechanisms, Clinical Efficacy, and Integration within the One Health Approach

by Charalampos Filippou, Sophia C. Themistocleous, Giorgos Marangos, Yiannis Panayiotou, Maria Fyrilla, Christina A. Kousparou, Zoi-Dorothea Pana, Constantinos Tsioutis, Elizabeth O. Johnson and Andreas Yiallouris

Int. J. Mol. Sci. 2024, 25(2), 1110; https://doi.org/10.3390/ijms25021110 - 16 Jan 2024

Cited by 1 | Viewed by 1690

Abstract

This comprehensive review elucidates the profound relationship between the human microbiome and breast cancer management. Recent findings highlight the significance of microbial alterations in tissue, such as the gut and the breast, and their role in influencing the breast cancer risk, development, progression, and treatment outcomes. We delve into how the gut microbiome can modulate systemic inflammatory responses and estrogen levels, thereby impacting cancer initiation and therapeutic drug efficacy. Furthermore, we explore the unique microbial diversity within breast tissue, indicating potential imbalances brought about by cancer and highlighting specific microbes as promising therapeutic targets. Emphasizing a holistic One Health approach, this review underscores the importance of integrating insights from human, animal, and environmental health to gain a deeper understanding of the complex microbe–cancer interplay. As the field advances, the strategic manipulation of the microbiome and its metabolites presents innovative prospects for the enhancement of cancer diagnostics and therapeutics. However, rigorous clinical trials remain essential to confirm the potential of microbiota-based interventions in breast cancer management. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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25 pages, 2193 KiB

Open AccessReview

Potential Application of Self-Assembled Peptides and Proteins in Breast Cancer and Cervical Cancer

by Shidong Zhang, Meiqi Chen, Zijun Geng, Tianjia Liu, Shuangyang Li, Qixuan Yu, Lingling Cao and Da Liu

Int. J. Mol. Sci. 2023, 24(23), 17056; https://doi.org/10.3390/ijms242317056 - 2 Dec 2023

Cited by 1 | Viewed by 1421

Abstract

Ongoing research is gradually broadening the idea of cancer treatment, with attention being focused on nanoparticles to improve the stability, therapeutic efficacy, targeting, and other important metrics of conventional drugs and traditional drug delivery methods. Studies have demonstrated that drug delivery carriers based on biomaterials (e.g., protein nanoparticles and lipids) and inorganic materials (e.g., metal nanoparticles) have potential anticancer effects. Among these carriers, self-assembled proteins and peptides, which are highly biocompatible and easy to standardize and produce, are strong candidates for the preparation of anticancer drugs. Breast cancer (BC) and cervical cancer (CC) are two of the most common and deadly cancers in women. These cancers not only threaten lives globally but also put a heavy burden on the healthcare system. Despite advances in medical care, the incidence of these two cancers, particularly CC, which is almost entirely preventable, continues to rise, and the mortality rate remains steady. Therefore, there is still a need for in-depth research on these two cancers to develop more targeted, efficacious, and safe therapies. This paper reviews the types of self-assembling proteins and peptides (e.g., ferritin, albumin, and virus-like particles) and natural products (e.g., soy and paclitaxel) commonly used in the treatment of BC and CC and describes the types of drugs that can be delivered using self-assembling proteins and peptides as carriers (e.g., siRNAs, DNA, plasmids, and mRNAs). The mechanisms (including self-assembly) by which the natural products act on CC and BC are discussed. The mechanism of action of natural products on CC and BC and the mechanism of action of self-assembled proteins and peptides have many similarities (e.g., NF-KB and Wnt). Thus, natural products using self-assembled proteins and peptides as carriers show potential for the treatment of BC and CC. Full article

(This article belongs to the Special Issue Molecular Biology of Breast Cancer)

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