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Molecular Research in Breast Cancer: Pathophysiology and Treatment
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Molecular Research in Breast Cancer: Pathophysiology and Treatment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 7451

Special Issue Editor

Dr. Costa Frangou

E-Mail Website
Guest Editor
Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Interests: breast cancer

Special Issue Information

Dear Colleagues,

Breast cancer is a complex, heterogeneous disease that can be divided into distinct clinical, histopathological, and molecular subtypes. Breast cancer survival rates have improved significantly in recent decades due to early detection, better screening, and improvements in treatment options; however, 20%–30% of breast cancers progress to recurrent or metastatic disease. Recently, it has been shown that breast cancer consists not only of neoplastic cells but also of alterations in the tumor microenvironment. These alterations are now recognized as critical in breast cancer development and progression. Questions remain as to why many types of breast cancer do not respond well to targeted treatments, particularly immunotherapy. Furthermore, targeted therapy for breast cancer also faces the challenges of increasing cancer care costs and the risk of overtreatment. Future progress in breast cancer treatment and diagnosis will require new molecular targets and diagnostic biomarkers in order to improve patient prognoses and therapy outcomes.

Dr. Costa Frangou
Guest Editor

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Keywords

  • breast
  • biomarker
  • early detection
  • immunotherapy
  • metastasis
  • microenvironment
  • outcomes
  • prognosis
  • relapse
  • treatment
  • tumor

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Published Papers (5 papers)

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Research

10 pages, 1580 KiB  
Article
Bcl-2 Up-Regulation Mediates Taxane Resistance Downstream of APC Loss
by Angelique R. Wise, Sara Maloney, Adam Hering, Sarah Zabala, Grace E. Richmond, Monica K. VanKlompenberg, Murlidharan T. Nair and Jenifer R. Prosperi
Int. J. Mol. Sci. 2024, 25(12), 6745; https://doi.org/10.3390/ijms25126745 - 19 Jun 2024
Viewed by 1068
Abstract
Triple-negative breast cancer (TNBC) patients are treated with traditional chemotherapy, such as the taxane class of drugs. One such drug, paclitaxel (PTX), can be effective in treating TNBC; however, many tumors will develop drug resistance, which can lead to recurrence. In order to [...] Read more.
Triple-negative breast cancer (TNBC) patients are treated with traditional chemotherapy, such as the taxane class of drugs. One such drug, paclitaxel (PTX), can be effective in treating TNBC; however, many tumors will develop drug resistance, which can lead to recurrence. In order to improve patient outcomes and survival, there lies a critical need to understand the mechanism behind drug resistance. Our lab made the novel observation that decreased expression of the Adenomatous Polyposis Coli (APC) tumor suppressor using shRNA caused PTX resistance in the human TNBC cell line MDA-MB-157. In cells lacking APC, induction of apoptosis by PTX was decreased, which was measured through cleaved caspase 3 and annexin/PI staining. The current study demonstrates that CRISPR-mediated APC knockout in two other TNBC lines, MDA-MB-231 and SUM159, leads to PTX resistance. In addition, the cellular consequences and molecular mechanisms behind APC-mediated PTX response have been investigated through analysis of the BCL-2 family of proteins. We found a significant increase in the tumor-initiating cell population and increased expression of the pro-survival family member Bcl-2, which is widely known for its oncogenic behavior. ABT-199 (Venetoclax), is a BH3 mimetic that specifically targets Bcl-2. ABT-199 has been used as a single or combination therapy in multiple hematologic malignancies and has shown promise in multiple subtypes of breast cancer. To address the hypothesis that APC-induced Bcl-2 increase is responsible for PTX resistance, we combined treatment of PTX and ABT-199. This combination treatment of CRISPR-mediated APC knockout MDA-MB-231 cells resulted in alterations in apoptosis, suggesting that Bcl-2 inhibition restores PTX sensitivity in APC knockout breast cancer cells. Our studies are the first to show that Bcl-2 functional inhibition restores PTX sensitivity in APC mutant breast cancer cells. These studies are critical to advance better treatment regimens in patients with TNBC. Full article
(This article belongs to the Special Issue Molecular Research in Breast Cancer: Pathophysiology and Treatment)
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16 pages, 1583 KiB  
Article
Triple-Negative Breast Cancer Subclassified by Immunohistochemistry: Correlation with Clinical and Pathological Outcomes in Patients Receiving Neoadjuvant Chemotherapy
by Bruno de Paula, Susanne Crocamo, Carlos Augusto Moreira de Sousa, Priscila Valverde, Fabiana Rezende and Eliana Abdelhay
Int. J. Mol. Sci. 2024, 25(11), 5825; https://doi.org/10.3390/ijms25115825 - 27 May 2024
Cited by 1 | Viewed by 1238
Abstract
The intrinsic subtype of triple-negative breast cancer (TNBC) is based on genomic evaluation. In this study, we report the survival and pathological complete response (pCR) rates of TNBC patients subtyped by IHC and treated with neoadjuvant chemotherapy (NACT). A retrospective cohort of 187 [...] Read more.
The intrinsic subtype of triple-negative breast cancer (TNBC) is based on genomic evaluation. In this study, we report the survival and pathological complete response (pCR) rates of TNBC patients subtyped by IHC and treated with neoadjuvant chemotherapy (NACT). A retrospective cohort of 187 TNBC patients who received NACT between 2008 and 2017 was used, and IHC subtyping was performed on biopsy specimens before chemotherapy. The subtyping revealed predominantly basal-like tumors (IHC-BL, 61%), followed by basal-like immune-suppressed tumors (IHC-BLIS, 31%), mesenchymal tumors (12.5%), luminal androgen receptor tumors (IHC-LAR, 12%), and basal-like immune-activated tumors (IHC-BLIA, 10.9%). The pCR rate varied among subtypes, with IHC-BLIA showing the highest (30.0%) and IHC-LAR showing the lowest (4.5%). IHC-BLIS led in recurrence sites. Overall and disease-free survival analyses did not show significant differences among subtypes, although IHC-BLIA demonstrated a trend toward better survival, and IHC-mesenchymal, worse. Patients who achieved pCR exhibited significantly better disease-free survival and overall survival than non-responders. This study underscores the potential of IHC-based subtyping in TNBC management, highlighting distinct response patterns to neoadjuvant chemotherapy and potential implications for treatment strategies. Further research is warranted to validate these findings and explore tailored therapeutic approaches for specific TNBC subtypes. Full article
(This article belongs to the Special Issue Molecular Research in Breast Cancer: Pathophysiology and Treatment)
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17 pages, 6923 KiB  
Article
MEF2D Functions as a Tumor Suppressor in Breast Cancer
by Xiaoxia Wang, He Shen, Yanmin Chen, Yali Zhang, Jianmin Wang, Song Liu, Bo Xu, Hai Wang, Costa Frangou and Jianmin Zhang
Int. J. Mol. Sci. 2024, 25(10), 5207; https://doi.org/10.3390/ijms25105207 - 10 May 2024
Viewed by 1100
Abstract
The myocyte enhancer factor 2 (MEF2) gene family play fundamental roles in the genetic programs that control cell differentiation, morphogenesis, proliferation, and survival in a wide range of cell types. More recently, these genes have also been implicated as drivers of carcinogenesis, by [...] Read more.
The myocyte enhancer factor 2 (MEF2) gene family play fundamental roles in the genetic programs that control cell differentiation, morphogenesis, proliferation, and survival in a wide range of cell types. More recently, these genes have also been implicated as drivers of carcinogenesis, by acting as oncogenes or tumor suppressors depending on the biological context. Nonetheless, the molecular programs they regulate and their roles in tumor development and progression remain incompletely understood. The present study evaluated whether the MEF2D transcription factor functions as a tumor suppressor in breast cancer. The knockout of the MEF2D gene in mouse mammary epithelial cells resulted in phenotypic changes characteristic of neoplastic transformation. These changes included enhanced cell proliferation, a loss of contact inhibition, and anchorage-independent growth in soft agar, as well as the capacity for tumor development in mice. Mechanistically, the knockout of MEF2D induced the epithelial-to-mesenchymal transition (EMT) and activated several oncogenic signaling pathways, including AKT, ERK, and Hippo-YAP. Correspondingly, a reduced expression of MEF2D was observed in human triple-negative breast cancer cell lines, and a low MEF2D expression in tissue samples was found to be correlated with a worse overall survival and relapse-free survival in breast cancer patients. MEF2D may, thus, be a putative tumor suppressor, acting through selective gene regulatory programs that have clinical and therapeutic significance. Full article
(This article belongs to the Special Issue Molecular Research in Breast Cancer: Pathophysiology and Treatment)
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15 pages, 2965 KiB  
Article
Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome
by Anna Seller, Christian M. Tegeler, Jonas Mauermann, Tatjana Schreiber, Ilona Hagelstein, Kai Liebel, André Koch, Jonas S. Heitmann, Sarah M. Greiner, Clara Hayn, Dominik Dannehl, Tobias Engler, Andreas D. Hartkopf, Markus Hahn, Sara Y. Brucker, Helmut R. Salih and Melanie Märklin
Int. J. Mol. Sci. 2024, 25(7), 4126; https://doi.org/10.3390/ijms25074126 - 8 Apr 2024
Cited by 3 | Viewed by 1849
Abstract
Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor [...] Read more.
Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study. Full article
(This article belongs to the Special Issue Molecular Research in Breast Cancer: Pathophysiology and Treatment)
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18 pages, 3354 KiB  
Article
miRNA-378 Is Downregulated by XBP1 and Inhibits Growth and Migration of Luminal Breast Cancer Cells
by Vahid Arabkari, David Barua, Muhammad Mosaraf Hossain, Mark Webber, Terry Smith, Ananya Gupta and Sanjeev Gupta
Int. J. Mol. Sci. 2024, 25(1), 186; https://doi.org/10.3390/ijms25010186 - 22 Dec 2023
Cited by 3 | Viewed by 1502
Abstract
X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is [...] Read more.
X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is well-characterised, emerging evidence suggests its involvement in endocrine resistance in breast cancer. The transcriptional activity of spliced XBP1 (XBP1s) is a major component of its biological effects, but the targets of XBP1s in estrogen receptor (ER)-positive breast cancer are not well understood. Here, we show that the expression of miR-378 and PPARGC1B (host gene of miR-378) is downregulated during UPR. Using chemical and genetic methods, we show that XBP1s is necessary and sufficient for the downregulation of miR-378 and PPARGC1B. Our results show that overexpression of miR-378 significantly suppressed cell growth, colony formation, and migration of ER-positive breast cancer cells. Further, we found that expression of miR-378 sensitised the cells to UPR-induced cell death and anti-estrogens. The expression of miR-378 and PPARGC1B was downregulated in breast cancer, and higher expression of miR-378 is associated with better outcomes in ER-positive breast cancer. We found that miR-378 upregulates the expression of several genes that regulate type I interferon signalling. Analysis of separate cohorts of breast cancer patients showed that a gene signature derived from miR-378 upregulated genes showed a strong association with improved overall and recurrence-free survival in breast cancer. Our results suggest a growth-suppressive role for miR-378 in ER-positive breast cancer where downregulation of miR-378 by XBP1 contributes to endocrine resistance in ER-positive breast cancer. Full article
(This article belongs to the Special Issue Molecular Research in Breast Cancer: Pathophysiology and Treatment)
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