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19 pages, 3810 KiB

Open AccessArticle

Targeting ITGβ3 to Overcome Trastuzumab Resistance through Epithelial–Mesenchymal Transition Regulation in HER2-Positive Breast Cancer

by Asiye Busra Boz Er and Idris Er

Int. J. Mol. Sci. 2024, 25(16), 8640; https://doi.org/10.3390/ijms25168640 - 8 Aug 2024

Cited by 8 | Viewed by 1301

Abstract

HER2-positive breast cancer, representing 15–20% of all breast cancer cases, often develops resistance to the HER2-targeted therapy trastuzumab. Unfortunately, effective treatments for advanced HER2-positive breast cancer remain scarce. This study aims to investigate the roles of ITGβ3, and Hedgehog signaling in trastuzumab resistance [...] Read more.

HER2-positive breast cancer, representing 15–20% of all breast cancer cases, often develops resistance to the HER2-targeted therapy trastuzumab. Unfortunately, effective treatments for advanced HER2-positive breast cancer remain scarce. This study aims to investigate the roles of ITGβ3, and Hedgehog signaling in trastuzumab resistance and explore the potential of combining trastuzumab with cilengitide as a therapeutic strategy. Quantitative gene expression analysis was performed to assess the transcription of EMT (epithelial–mesenchymal transition) markers Slug, Snail, Twist2, and Zeb1 in trastuzumab-resistant HER2-positive breast cancer cells. The effects of ITGβ3 and Hedgehog signaling were investigated. Additionally, the combination therapy of trastuzumab and cilengitide was evaluated. Acquired trastuzumab resistance induced the transcription of Slug, Snail, Twist2, and Zeb1, indicating increased EMT. This increased EMT was mediated by ITGB3 and Hedgehog signaling. ITGβ3 regulated both the Hedgehog pathway and EMT, with the latter being independent of the Hedgehog pathway. The combination of trastuzumab and cilengitide showed a synergistic effect, reducing both EMT and Hedgehog pathway activity. Targeting ITGβ3 with cilengitide, combined with trastuzumab, effectively suppresses the Hedgehog pathway and EMT, offering a potential strategy to overcome trastuzumab resistance and improve outcomes for HER2-positive breast cancer patients. Full article

(This article belongs to the Special Issue Advances and Mechanisms in Breast Cancer)

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14 pages, 2979 KiB

Open AccessArticle

Tumor-Intrinsic Enhancer of Zeste Homolog 2 Controls Immune Cell Infiltration, Tumor Growth, and Lung Metastasis in a Triple-Negative Breast Cancer Model

by Lenore Monterroza, Maria M. Parrilla, Sarah G. Samaranayake, Dormarie E. Rivera-Rodriguez, Sung Bo Yoon, Ramireddy Bommireddy, Justin Hosten, Luisa Cervantes Barragan, Adam Marcus, Brian S. Dobosh, Periasamy Selvaraj and Rabindra Tirouvanziam

Int. J. Mol. Sci. 2024, 25(10), 5392; https://doi.org/10.3390/ijms25105392 - 15 May 2024

Cited by 2 | Viewed by 2068

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic type of tumor. TNBC is often enriched in tumor-infiltrating neutrophils (TINs), which support cancer growth in part by counteracting tumor-infiltrating lymphocytes (TILs). Prior studies identified the enhancer of zeste homolog 2 (EZH2) as [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic type of tumor. TNBC is often enriched in tumor-infiltrating neutrophils (TINs), which support cancer growth in part by counteracting tumor-infiltrating lymphocytes (TILs). Prior studies identified the enhancer of zeste homolog 2 (EZH2) as a pro-tumor methyltransferase in primary and metastatic TNBCs. We hypothesized that EZH2 inhibition in TNBC cells per se would exert antitumor activity by altering the tumor immune microenvironment. To test this hypothesis, we used CRISPR to generate EZH2 gene knockout (KO) and overexpressing (OE) lines from parent (wild-type—WT) 4T1 cells, an established murine TNBC model, resulting in EZH2 protein KO and OE, respectively. In vitro, EZH2 KO and OE cells showed early, transient changes in replicative capacity and invasiveness, and marked changes in surface marker profile and cytokine/chemokine secretion compared to WT cells. In vivo, EZH2 KO cells showed significantly reduced primary tumor growth and a 10-fold decrease in lung metastasis compared to WT cells, while EZH2 OE cells were unchanged. Compared to WT tumors, TIN:TIL ratios were greatly reduced in EZH2 KO tumors but unchanged in EZH2 OE tumors. Thus, EZH2 is key to 4T1 aggressiveness as its tumor-intrinsic knockout alters their in vitro secretome and in vivo primary tumor growth, TIN/TIL poise, and metastasis. Full article

(This article belongs to the Special Issue Advances and Mechanisms in Breast Cancer)

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15 pages, 5891 KiB

Open AccessArticle

Resistance to Combined Anthracycline–Taxane Chemotherapy Is Associated with Altered Metabolism and Inflammation in Breast Carcinomas

by Otília Menyhárt, János Tibor Fekete and Balázs Győrffy

Int. J. Mol. Sci. 2024, 25(2), 1063; https://doi.org/10.3390/ijms25021063 - 15 Jan 2024

Cited by 2 | Viewed by 2403

Abstract

Approximately 30% of early-stage breast cancer (BC) patients experience recurrence after systemic chemotherapy; thus, understanding therapy resistance is crucial in developing more successful treatments. Here, we investigated the mechanisms underlying resistance to combined anthracycline–taxane treatment by comparing gene expression patterns with subsequent therapeutic [...] Read more.

Approximately 30% of early-stage breast cancer (BC) patients experience recurrence after systemic chemotherapy; thus, understanding therapy resistance is crucial in developing more successful treatments. Here, we investigated the mechanisms underlying resistance to combined anthracycline–taxane treatment by comparing gene expression patterns with subsequent therapeutic responses. We established a cohort of 634 anthracycline–taxane-treated patients with pathological complete response (PCR) and a separate cohort of 187 patients with relapse-free survival (RFS) data, each having transcriptome-level expression data of 10,017 unique genes. Patients were categorized as responders and non-responders based on their PCR and RFS status, and the expression for each gene was compared between the two groups using a Mann–Whitney U-test. Statistical significance was set at p < 0.05, with fold change (FC) > 1.44. Altogether, 224 overexpressed genes were identified in the tumor samples derived from the patients without PCR; among these, the gene sets associated with xenobiotic metabolism (e.g., CYP3A4, CYP2A6) exhibited significant enrichment. The genes ORAI3 and BCAM differentiated non-responders from responders with the highest AUC values (AUC > 0.75, p < 0.0001). We identified 51 upregulated genes in the tumor samples derived from the patients with relapse within 60 months, participating primarily in inflammation and innate immune responses (e.g., LYN, LY96, ANXA1). Furthermore, the amino acid transporter SLC7A5, distinguishing non-responders from responders, had significantly higher expression in tumors and metastases than in normal tissues (Kruskal–Wallis p = 8.2 × 10⁻²⁰). The identified biomarkers underscore the significance of tumor metabolism and microenvironment in treatment resistance and can serve as a foundation for preclinical validation studies. Full article

(This article belongs to the Special Issue Advances and Mechanisms in Breast Cancer)

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15 pages, 5369 KiB

Open AccessArticle

The Role of Transcription Factors in the Loss of Inter-Chromosomal Co-Expression for Breast Cancer Subtypes

by Rodrigo Trujillo-Ortíz, Jesús Espinal-Enríquez and Enrique Hernández-Lemus

Int. J. Mol. Sci. 2023, 24(24), 17564; https://doi.org/10.3390/ijms242417564 - 16 Dec 2023

Cited by 1 | Viewed by 1407

Abstract

Breast cancer encompasses a diverse array of subtypes, each exhibiting distinct clinical characteristics and treatment responses. Unraveling the underlying regulatory mechanisms that govern gene expression patterns in these subtypes is essential for advancing our understanding of breast cancer biology. Gene co-expression networks (GCNs) [...] Read more.

Breast cancer encompasses a diverse array of subtypes, each exhibiting distinct clinical characteristics and treatment responses. Unraveling the underlying regulatory mechanisms that govern gene expression patterns in these subtypes is essential for advancing our understanding of breast cancer biology. Gene co-expression networks (GCNs) help us identify groups of genes that work in coordination. Previous research has revealed a marked reduction in the interaction of genes located on different chromosomes within GCNs for breast cancer, as well as for lung, kidney, and hematopoietic cancers. However, the reasons behind why genes on the same chromosome often co-express remain unclear. In this study, we investigate the role of transcription factors in shaping gene co-expression networks within the four main breast cancer subtypes: Luminal A, Luminal B, HER2+, and Basal, along with normal breast tissue. We identify communities within each GCN and calculate the transcription factors that may regulate these communities, comparing the results across different phenotypes. Our findings indicate that, in general, regulatory behavior is to a large extent similar among breast cancer molecular subtypes and even in healthy networks. This suggests that transcription factor motif usage does not fully determine long-range co-expression patterns. Specific transcription factor motifs, such as CCGGAAG, appear frequently across all phenotypes, even involving multiple highly connected transcription factors. Additionally, certain transcription factors exhibit unique actions in specific subtypes but with limited influence. Our research demonstrates that the loss of inter-chromosomal co-expression is not solely attributable to transcription factor regulation. Although the exact mechanism responsible for this phenomenon remains elusive, this work contributes to a better understanding of gene expression regulatory programs in breast cancer. Full article

(This article belongs to the Special Issue Advances and Mechanisms in Breast Cancer)

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Review

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17 pages, 544 KiB

Open AccessReview

Harnessing Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Opportunities and Barriers to Clinical Integration

by Cara Coleman, Tharakeswari Selvakumar, Aswani Thurlapati, Kevin Graf, Sushma Pavuluri, Shikhar Mehrotra, Ozgur Sahin and Abirami Sivapiragasam

Int. J. Mol. Sci. 2025, 26(9), 4292; https://doi.org/10.3390/ijms26094292 - 1 May 2025

Viewed by 432

Abstract

Triple-negative breast cancer (TNBC) continues to present a therapeutic challenge due to the fact that by definition, these cancer cells lack the expression of targetable receptors. Current treatment options include cytotoxic chemotherapy, antibody–drug conjugates (ADC), and the PD-1 checkpoint inhibitor, pembrolizumab. Due to [...] Read more.

Triple-negative breast cancer (TNBC) continues to present a therapeutic challenge due to the fact that by definition, these cancer cells lack the expression of targetable receptors. Current treatment options include cytotoxic chemotherapy, antibody–drug conjugates (ADC), and the PD-1 checkpoint inhibitor, pembrolizumab. Due to high rates of recurrence, current guidelines for early-stage TNBC recommend either multi-agent chemotherapy or chemo–immunotherapy in all patients other than those with node-negative tumors < 0.5 cm. This approach can lead to significant long-term effects for TNBC survivors, driving a growing interest in de-escalating therapy where appropriate. Tumor infiltrating lymphocytes (TILs) represent a promising prognostic and predictive biomarker for TNBC. These diverse immune cells are present in the tumor microenvironment and within the tumor itself, and multiple retrospective studies have demonstrated that a higher number of TILs in early-stage TNBC portends a favorable prognosis. Research has also explored the potential of TIL scores to predict the response to immunotherapy. However, several barriers to the widespread use of TILs in clinical practice remain, including logistical and technical challenges with the scoring of TILs and lack of prospective trials to validate the trends seen in retrospective studies. This review will present the current understanding of the role of TILs in TNBC and discuss the future directions of TIL research. Full article

(This article belongs to the Special Issue Advances and Mechanisms in Breast Cancer)

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34 pages, 1392 KiB

Open AccessReview

Understanding Susceptibility to Breast Cancer: From Risk Factors to Prevention Strategies

by Natalia García-Sancha, Roberto Corchado-Cobos and Jesús Pérez-Losada

Int. J. Mol. Sci. 2025, 26(7), 2993; https://doi.org/10.3390/ijms26072993 - 25 Mar 2025

Viewed by 1126

Abstract

Breast cancer is the most common malignancy among women globally, with incidence rates continuing to rise. A comprehensive understanding of its risk factors and the underlying biological mechanisms that drive tumor initiation is essential for developing effective prevention strategies. This review examines key [...] Read more.

Breast cancer is the most common malignancy among women globally, with incidence rates continuing to rise. A comprehensive understanding of its risk factors and the underlying biological mechanisms that drive tumor initiation is essential for developing effective prevention strategies. This review examines key non-modifiable risk factors, such as genetic predisposition, demographic characteristics, family history, mammographic density, and reproductive milestones, as well as modifiable risk factors like exogenous hormone exposure, obesity, diet, and physical inactivity. Importantly, reproductive history plays a dual role, providing long-term protection while temporarily increasing breast cancer risk shortly after pregnancy. Current chemoprevention strategies primarily depend on selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, which have demonstrated efficacy in reducing the incidence of estrogen receptor-positive breast cancer but remain underutilized due to adverse effects. Emerging approaches such as aromatase inhibitors, RANKL inhibitors, progesterone antagonists, PI3K inhibitors, and immunoprevention strategies show promise for expanding preventive options. Understanding the interactions between risk factors, hormonal influences, and tumorigenesis is critical for optimizing breast cancer prevention and advancing safer, more targeted chemopreventive interventions Full article

(This article belongs to the Special Issue Advances and Mechanisms in Breast Cancer)

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23 pages, 3640 KiB

Open AccessReview

The “Forgotten” Subtypes of Breast Carcinoma: A Systematic Review of Selected Histological Variants Not Included or Not Recognized as Distinct Entities in the Current World Health Organization Classification of Breast Tumors

by Nektarios I. Koufopoulos, Ioannis Boutas, Abraham Pouliakis, Menelaos G. Samaras, Christakis Kotanidis, Adamantia Kontogeorgi, Dionysios T. Dimas, Argyro-Ioanna Ieronimaki, Danai Leventakou, Aris Spathis, Magda Zanelli, Andrea Palicelli, Maurizio Zizzo, Dimitrios Goutas, Ioannis S. Pateras and Ioannis G. Panayiotides

Int. J. Mol. Sci. 2024, 25(15), 8382; https://doi.org/10.3390/ijms25158382 - 1 Aug 2024

Cited by 3 | Viewed by 1938

Abstract

Breast carcinoma is the most common cancer in women. Nineteen different subtypes of breast carcinomas are recognized in the current WHO classification of breast tumors. Except for these subtypes, there are a number of carcinomas with special morphologic and immunohistochemical features that are [...] Read more.

Breast carcinoma is the most common cancer in women. Nineteen different subtypes of breast carcinomas are recognized in the current WHO classification of breast tumors. Except for these subtypes, there are a number of carcinomas with special morphologic and immunohistochemical features that are not included in the 5th WHO classification, while others are considered special morphologic patterns of invasive breast carcinoma of no special type. In this manuscript, we systematically review the literature on four different subtypes of invasive breast carcinoma, namely lymphoepithelioma-like breast carcinoma, breast carcinoma with osteoclast-like giant cells, signet-ring breast carcinoma, and metaplastic breast carcinoma with melanocytic differentiation. We describe their clinicopathological characteristics, focusing on the differential diagnosis, treatment, and prognosis. Full article

(This article belongs to the Special Issue Advances and Mechanisms in Breast Cancer)

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13 pages, 1027 KiB

Open AccessReview

Reverse Onco-Cardiology: What Is the Evidence for Breast Cancer? A Systematic Review of the Literature

by Ioannis Boutas, Adamantia Kontogeorgi, Sophia N. Kalantaridou, Constantine Dimitrakakis, Panagiotis Patsios, Maria Kalantzi and Theodoros Xanthos

Int. J. Mol. Sci. 2023, 24(22), 16500; https://doi.org/10.3390/ijms242216500 - 19 Nov 2023

Cited by 3 | Viewed by 3112

Abstract

Breast cancer and cardiovascular diseases (CVD) represent significant global health challenges, with CVD being the leading cause of mortality and breast cancer, showing a complex pattern of incidence and mortality. We explore the intricate interplay between these two seemingly distinct medical conditions, shedding [...] Read more.

Breast cancer and cardiovascular diseases (CVD) represent significant global health challenges, with CVD being the leading cause of mortality and breast cancer, showing a complex pattern of incidence and mortality. We explore the intricate interplay between these two seemingly distinct medical conditions, shedding light on their shared risk factors and potential pathophysiological connections. A specific connection between hypertension (HTN), atrial fibrillation (AF), myocardial infarction (MI), and breast cancer was evaluated. HTN is explored in detail, emphasizing the role of aging, menopause, insulin resistance, and obesity as common factors linking HTN and breast cancer. Moreover, an attempt is made to identify the potential impact of antihypertensive medications and highlight the increased risk of breast cancer among those women, with a focus on potential mechanisms. A summary of key findings underscores the need for a multisystem approach to understanding the relationship between CVD and breast cancer is also explored with a highlight for all the gaps in current research, such as the lack of clinical observational data on MI and breast cancer in humans and the need for studies specifically designed for breast cancer. This paper concludes that there should be a focus on potential clinical applications of further investigation in this field, including personalized prevention and screening strategies for women at risk. Overall, the authors attempt to provide a comprehensive overview of the intricate connections between breast cancer and cardiovascular diseases, emphasizing the importance of further research in this evolving field of cardio-oncology. Full article

(This article belongs to the Special Issue Advances and Mechanisms in Breast Cancer)

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