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Molecular Research and Treatment of Breast Cancer 2.0

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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 (15 September 2023) | Viewed by 18625

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Dr. Anna Kawiak

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Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, 80-307 Gdansk, Poland
Interests: apoptosis; cancer cell biology; cell signaling; drug discovery; drug resistance
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Dear Colleagues,

Breast cancer is one of the most frequently diagnosed malignancies in the female population. Due to its heterogeneity, the molecular mechanisms governing breast cancer development and progression are complex and impact prognosis and treatment efficacy. Advances in the field of molecular research have offered insight into the cellular mechanisms and genetic changes that characterize breast cancer subtypes. This has enabled the identification of key driver genes and aberrations that initiate tumor development and the delineation of signaling pathway alterations underlying breast tumor growth. Furthermore, the characterization of novel cellular targets has significantly contributed to the development of improved therapeutic and diagnostic strategies.

This Special Issue of IJMS will welcome original research and review articles with the aim of providing an overview of advances on the molecular bases of breast cancer. Research within this Issue will focus on the molecular aspects of breast cancer development, progression and invasion. The development and discovery of therapeutic agents, as well as strategies that increase the efficacy of standard therapy, will also be covered. Additionally, research related to therapy resistance and approaches that target tumor escape mechanisms will be included in the scope of this Issue.

Dr. Anna Kawiak
Guest Editor

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Keywords

biomarkers
breast cancer
cancer stem cells
cell signaling
circulating tumor cells
drug discovery
molecular diagnostics
molecular profiling
targeted therapy
therapy resistance

Related Special Issue

Molecular Research and Treatment of Breast Cancer 3.0 in International Journal of Molecular Sciences (2 articles)

Published Papers (10 papers)

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Editorial

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5 pages, 187 KiB

Open AccessEditorial

Molecular Research and Treatment of Breast Cancer 2.0

by Anna Kawiak

Int. J. Mol. Sci. 2024, 25(7), 3932; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25073932 - 01 Apr 2024

Viewed by 459

Abstract

Breast cancer is the primary contributor to cancer-related deaths among women [...] Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

Research

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20 pages, 6863 KiB

Open AccessArticle

YTHDF1’s Regulatory Involvement in Breast Cancer Prognosis, Immunity, and the ceRNA Network

by Wenting Luo, Youjia Zhou, Jiayang Wang, Keqin Wang, Qing Lin, Yuqiu Li, Yujie Xie, Miao Li, Jie Wang and Lixia Xiong

Int. J. Mol. Sci. 2024, 25(3), 1879; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25031879 - 04 Feb 2024

Cited by 1 | Viewed by 866

Abstract

YTH N⁶-methyladenosine RNA binding protein 1 (YTHDF1), an m6A reader, has a role in the development and progression of breast cancer as well as the immunological microenvironment. The networks of competing endogenous RNA in cancer have received much attention in research. In tumor gene therapy, the regulatory networks of m6A and competing endogenous RNA are increasingly emerging as a new route. We evaluated the relationship between the YTHDF1 expression, overall survival, and clinicopathology of breast cancer using TCGA, PrognoScan, and other datasets. We used Western blot to demonstrate that YTHDF1 is substantially expressed in breast cancer tissues. Furthermore, we explored YTHDF1′s functions in the tumor mutational burden, microsatellite instability, and tumor microenvironment. Our findings indicate that YTHDF1 is a critical component of the m6A regulatory proteins in breast cancer and may have a particular function in the immunological microenvironment. Crucially, we investigated the relationship between YTHDF1 and the associated competitive endogenous RNA regulatory networks, innovatively creating three such networks (Dehydrogenase/Reductase 4-Antisense RNA 1-miR-378g-YTHDF1, HLA Complex Group 9-miR-378g-YTHDF1, Taurine Up-regulated 1-miR-378g-YTHDF1). Furthermore, we showed that miR-378g could inhibit the expression of YTHDF1, and that miR-378g/YTHDF1 could impact MDA-MB-231 proliferation. We speculate that YTHDF1 may serve as a biomarker for poor prognosis and differential diagnosis, impact the growth of breast cancer cells via the ceRNA network axis, and be a target for immunotherapy against breast cancer. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

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15 pages, 2466 KiB

Open AccessArticle

Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer

by Polina Kaidun, Samuel J. Holzmayer, Sarah M. Greiner, Anna Seller, Christian M. Tegeler, Ilona Hagelstein, Jonas Mauermann, Tobias Engler, André Koch, Andreas D. Hartkopf, Helmut R. Salih and Melanie Märklin

Int. J. Mol. Sci. 2023, 24(17), 13156; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713156 - 24 Aug 2023

Cited by 2 | Viewed by 1551

Abstract

Triple–negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from healthy tissues; thus, they are promising tumor antigens for novel immunotherapeutic approaches. We developed bispecific fusion proteins (BFPs) consisting of the NKG2D receptor domain targeting multiple NKG2DLs, fused to either anti–CD3 (NKG2D–CD3) or anti–CD16 (NKG2D–CD16) Fab fragments. First, we characterized the expression of the NKG2DLs (MICA, MICB, ULBP1–4) on TNBC cell lines and observed the highest surface expression for MICA and ULBP2. Targeting TNBC cells with NKG2D–CD3/CD16 efficiently activated both NK and T cells, leading to their degranulation and cytokine release and lysis of TNBC cells. Furthermore, PBMCs from TNBC patients currently undergoing chemotherapy showed significantly higher NK and T cell activation and tumor cell lysis when stimulated with NKG2D–CD3/CD16. In conclusions, BFPs activate and direct the NK and T cells of healthy and TNBC patients against TNBC cells, leading to efficient eradication of tumor cells. Therefore, NKG2D–based NK and T cell engagers could be a valuable addition to the treatment options for TNBC patients. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

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18 pages, 2778 KiB

Open AccessArticle

The Role of Irisin/FNDC5 Expression and Its Serum Level in Breast Cancer

by Kamil Cebulski, Aleksandra Piotrowska, Alicja Kmiecik, Katarzyna Haczkiewicz-Leśniak, Urszula Ciesielska, Jędrzej Grzegrzółka, Karolina Jabłońska, Hanna Romanowicz, Beata Smolarz, Piotr Dzięgiel, Marzenna Podhorska-Okołów and Katarzyna Nowińska

Int. J. Mol. Sci. 2023, 24(10), 8628; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108628 - 11 May 2023

Cited by 3 | Viewed by 1648

Abstract

Irisin (Ir) is an adipomyokine formed from fibronectin type III domain-containing protein 5 (FNDC5), which can be found in various cancer tissues. Additionally, FNDC5/Ir is suspected of inhibiting the epithelial-mesenchymal transition (EMT) process. This relationship has been poorly studied for breast cancer (BC). The ultrastructural cellular localizations of FNDC5/Ir were examined in BC tissues and BC cell lines. Furthermore, we compared serum levels of Ir with FNDC5/Ir expression in BC tissues. The aim of this study was to examine the levels of EMT markers, such as E-cadherin, N-cadherin, SNAIL, SLUG, and TWIST, and to compare their expression levels with FNDC5/Ir in BC tissues. Tissue microarrays with 541 BC samples were used to perform immunohistochemical reactions. Serum levels of Ir were assessed in 77 BC patients. We investigated FNDC5/Ir expression and ultrastructural localization in MCF-7, MDA-MB-231, and MDA-MB-468 BC cell lines and in the normal breast cell line (Me16c), which was used as the control. FNDC5/Ir was present in BC cell cytoplasm and tumor fibroblasts. FNDC5/Ir expression levels in BC cell lines were higher compared to those in the normal breast cell line. Serum Ir levels did not correlate with FNDC5/Ir expression in BC tissues but were associated with lymph node metastasis (N) and histological grade (G). We found that FNDC5/Ir correlated moderately with E-cadherin and SNAIL. Higher Ir serum level is associated with lymph node metastasis and increased grade of malignancy. FNDC5/Ir expression is associated with E-cadherin expression level. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

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18 pages, 3042 KiB

Open AccessArticle

Checkpoint Kinase 2 Inhibition Can Reverse Tamoxifen Resistance in ER-Positive Breast Cancer

by Ho Tsoi, Wai-Chung Tsang, Ellen P. S. Man, Man-Hong Leung, Chan-Ping You, Sum-Yin Chan, Wing-Lok Chan and Ui-Soon Khoo

Int. J. Mol. Sci. 2022, 23(20), 12290; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012290 - 14 Oct 2022

Cited by 3 | Viewed by 2044

Abstract

Breast cancer is a heterogeneous disease. Tamoxifen is frequently used to treat ER-positive breast cancer. Our team has identified a novel splice variant of NCOR2, BQ323636.1 (BQ), that mediates tamoxifen resistance. However, the upstream factors that modulate BQ expression are not apparent. This study reveals that tamoxifen treatment causes induction of DNA damage which can enhance BQ expression. We show that DNA damage can activate the ATM/CHK2 and ATR/CHK1 signalling cascades and confirm that ATM/CHK2 signalling is responsible for enhancing the protein stability of BQ. siRNA or a small inhibitor targeting CHK2 resulted in the reduction in BQ expression through reduced phosphorylation and enhanced poly-ubiquitination of BQ. Inhibition of CHK2 by CCT241533 could reverse tamoxifen resistance in vitro and in vivo. Using clinical samples in the tissue microarray, we confirmed that high p-CHK2 expression was significantly associated with high nuclear BQ expression, tamoxifen resistance and poorer overall and disease-specific survival. In conclusion, tamoxifen treatment can enhance BQ expression in ER-positive breast cancer by activating the ATM/CHK2 axis. Targeting CHK2 is a promising approach to overcoming tamoxifen resistance in ER-positive breast cancer. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

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19 pages, 3185 KiB

Open AccessArticle

Comprehensive Transcriptomic and Proteomic Analyses Identify a Candidate Gene Set in Cross-Resistance for Endocrine Therapy in Breast Cancer

by Chung-Liang Li, Sin-Hua Moi, Huei-Shan Lin, Ming-Feng Hou, Fang-Ming Chen, Shen-Liang Shih, Jung-Yu Kan, Chieh-Ni Kao, Yi-Chia Wu, Li-Chun Kao, Ying-Hsuan Chen, Yi-Chen Lee and Chih-Po Chiang

Int. J. Mol. Sci. 2022, 23(18), 10539; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810539 - 11 Sep 2022

Cited by 2 | Viewed by 2003

Abstract

Endocrine therapy (ET) of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs) has been used as the gold standard treatment for hormone-receptor-positive (HR+) breast cancer. Despite its clinical benefits, approximately 30% of patients develop ET resistance, which remains a major clinical challenge in patients with HR+ breast cancer. The mechanisms of ET resistance mainly focus on mutations in the ER and related pathways; however, other targets still exist from ligand-independent ER reactivation. Moreover, mutations in the ER that confer resistance to SERMs or AIs seldom appear in SERDs. To date, little research has been conducted to identify a critical target that appears in both SERMs/SERDs and AIs. In this study, we conducted comprehensive transcriptomic and proteomic analyses from two cohorts of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) to identify the critical targets for both SERMs/SERDs and AIs of ET resistance. From a treatment response cohort with treatment response for the initial ET regimen and an endocrine therapy cohort with survival outcomes, we identified candidate gene sets that appeared in both SERMs/SERDs and AIs of ET resistance. The candidate gene sets successfully differentiated progress/resistant groups (PD) from complete response groups (CR) and were significantly correlated with survival outcomes in both cohorts. In summary, this study provides valuable clinical implications for the critical roles played by candidate gene sets in the diagnosis, mechanism, and therapeutic strategy for both SERMs/SERDs and AIs of ET resistance for the future. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

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17 pages, 2193 KiB

Open AccessArticle

CYP1B1 Augments the Mesenchymal, Claudin-Low, and Chemoresistant Phenotypes of Triple-Negative Breast Cancer Cells

by Paul R. Hollis, Robert J. Mobley, Jyoti Bhuju, Amy N. Abell, Carrie Hayes Sutter and Thomas R. Sutter

Int. J. Mol. Sci. 2022, 23(17), 9670; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179670 - 26 Aug 2022

Cited by 4 | Viewed by 2711

Abstract

Cytochrome P4501B1 (CYP1B1) is elevated in breast cancer. Studies indicate a relationship between CYP1B1 and aggressive cancer phenotypes. Here, we report on in vitro studies in triple-negative breast cancer cell lines, where knockdown (KD) of CYP1B1 was used to determine the influence of its expression on invasive cell phenotypes. CYP1B1 KD in MDA-MB-231 cells resulted in the loss of mesenchymal morphology, altered expression of epithelial–mesenchymal genes, and increased claudin (CLDN) RNA and protein. CYP1B1 KD cells had increased cell-to-cell contact and paracellular barrier function, a reduced rate of cell proliferation, abrogation of migratory and invasive activity, and diminished spheroid formation. Analysis of clinical breast cancer tumor samples revealed an association between tumors exhibiting higher CYP1B1 RNA levels and diminished overall and disease-free survival. Tumor expression of CYP1B1 was inversely associated with CLDN7 expression, and CYP1B1^HI/CLDN7^LOW identified patients with lower median survival. Cells with CYP1B1 KD had an enhanced chemosensitivity to paclitaxel, 5-fluorouracil, and cisplatin. Our findings that CYP1B1 KD can increase chemosensitivity points to therapeutic targeting of this enzyme. CYP1B1 inhibitors in combination with chemotherapeutic drugs may provide a novel targeted and effective approach to adjuvant or neoadjuvant therapy against certain forms of highly metastatic breast cancer. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

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Review

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13 pages, 563 KiB

Open AccessReview

Unraveling the Intricate Link: Deciphering the Role of the Golgi Apparatus in Breast Cancer Progression

by Adrian Vasile Dumitru, Evelina-Elena Stoica, Razvan-Adrian Covache-Busuioc, Bogdan-Gabriel Bratu and Monica-Mihaela Cirstoiu

Int. J. Mol. Sci. 2023, 24(18), 14073; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241814073 - 14 Sep 2023

Cited by 1 | Viewed by 1332

Abstract

Breast cancer represents a paramount global health challenge, warranting intensified exploration of the molecular underpinnings influencing its progression to facilitate the development of precise diagnostic instruments and customized therapeutic regimens. Historically, the Golgi apparatus has been acknowledged for its primary role in protein sorting and trafficking within cellular contexts. However, recent findings suggest a potential link between modifications in Golgi apparatus function and organization and the pathogenesis of breast cancer. This review delivers an exhaustive analysis of this correlation. Specifically, we examine the consequences of disrupted protein glycosylation, compromised protein transport, and inappropriate oncoprotein processing on breast cancer cell dynamics. Furthermore, we delve into the impacts of Golgi-mediated secretory routes on the release of pro-tumorigenic factors during the course of breast cancer evolution. Elucidating the nuanced interplay between the Golgi apparatus and breast cancer can pave the way for innovative therapeutic interventions and the discovery of biomarkers, potentially enhancing the diagnostic, prognostic, and therapeutic paradigms for afflicted patients. The advancement of such research could substantially expedite the realization of these objectives. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

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13 pages, 1132 KiB

Open AccessReview

The Potential Role of Epigallocatechin-3-Gallate (EGCG) in Breast Cancer Treatment

by Víctor Marín, Viviana Burgos, Rebeca Pérez, Durvanei Augusto Maria, Paulo Pardi and Cristian Paz

Int. J. Mol. Sci. 2023, 24(13), 10737; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310737 - 27 Jun 2023

Cited by 2 | Viewed by 2262

Abstract

Breast cancer is one of the most diagnosed cancers worldwide, with an incidence of 47.8%. Its treatment includes surgery, radiotherapy, chemotherapy, and antibodies giving a mortality of 13.6%. Breast tumor development is driven by a variety of signaling pathways with high heterogeneity of surface receptors, which makes treatment difficult. Epigallocatechin-3-gallate (EGCG) is a natural polyphenol isolated as the main component in green tea; it has shown multiple beneficial effects in breast cancer, controlling proliferation, invasion, apoptosis, inflammation, and demethylation of DNA. These properties were proved in vitro and in vivo together with synergistic effects in combination with traditional chemotherapy, increasing the effectiveness of the treatment. This review focuses on the effects of EGCG on the functional capabilities acquired by breast tumor cells during its multistep development, the molecular and signal pathways involved, the synergistic effects in combination with current drugs, and how nanomaterials can improve its bioavailability on breast cancer treatment. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

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14 pages, 1059 KiB

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Modulating the Activity of Androgen Receptor for Treating Breast Cancer

by Chan-Ping You, Ho Tsoi, Ellen P. S. Man, Man-Hong Leung and Ui-Soon Khoo

Int. J. Mol. Sci. 2022, 23(23), 15342; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315342 - 05 Dec 2022

Cited by 7 | Viewed by 2642

Abstract

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cancer, blocking the AR could confer better prognosis to patients. These studies support the feasibility of utilizing AR modulators as anti-cancer drugs for different subtypes of breast cancer patients. Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer 2.0)

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