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Breast Cancer: From Pathophysiology to Novel Therapies
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Breast Cancer: From Pathophysiology to Novel Therapies

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: 20 June 2025 | Viewed by 4744

Special Issue Editor

Dr. Jennifer Sims-Mourtada

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Guest Editor
Helen F. Graham Cancer Center, Newark, DE, USA
Interests: triple-negative breast cancer; tumor microenvironment; humoral immunity; chemo/radiation response

Special Issue Information

Dear Colleagues,

Advancements in breast cancer research are increasingly focused on the interplay between genetics and the tumor microenvironment (TME). Understanding the genetic mutations and variations that drive breast cancer helps identify targets for novel therapies. The TME, which includes immune cells, stromal cells, and extracellular matrix, also plays a crucial role in stemness, tumor progression, and response to treatment. New model systems, such as patient-derived organoids, strive to replicate the complexity of breast tumors and their microenvironments, enabling more accurate drug screening and personalized therapy development. These organoids retain the genetic and histological features of the original tumors, providing insights into how genetic factors and TME interactions influence cancer behavior and treatment efficacy. By integrating genetic information and TME dynamics, researchers can develop targeted treatments that improve outcomes for breast cancer patients, including those with aggressive subtypes like triple-negative breast cancer (TNBC).

In this Special Issue, we seek original studies on all aspects of breast cancer research related to mechanisms driving stemness, tumor growth, and metastasis, with an emphasis on interactions between genetics and the tumor microenvironment and new model systems to identify and screen novel therapies.

Dr. Jennifer Sims-Mourtada
Guest Editor

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Keywords

  • breast cancer
  • genetics
  • tumor microenvironment
  • model systems
  • organoids
  • immune cells
  • tumor stroma
  • therapeutic resistance
  • novel therapies

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Published Papers (6 papers)

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Research

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16 pages, 2733 KiB  
Article
Ergosterol Peroxide Disrupts Triple-Negative Breast Cancer Mitochondrial Function and Inhibits Tumor Growth and Metastasis
by Aliyah L. Bocachica-Adorno, Adriana Y. Aponte-Ramos, Paola S. Rivera-Fuentes, Natalia P. Espinosa-Ponce, Luz V. Arroyo-Cruz, Taotao Ling, Naydi Pérez-Ríos, Sona Rivas-Tumanyan, Israel A. Almodóvar-Rivera, Carlos Barreto-Gamarra, Maribella Domenech-García, Fatima Rivas and Michelle M. Martínez-Montemayor
Int. J. Mol. Sci. 2025, 26(10), 4588; https://doi.org/10.3390/ijms26104588 (registering DOI) - 10 May 2025
Abstract
Ergosterol peroxide (EP) triggers apoptosis pathways by inducing reactive oxygen species (ROS) in TNBC cell lines. Excess ROS production is associated with major damage to mitochondria. We hypothesized that EP may act through ROS-induced mitochondrial dysfunction. Therefore, we performed a series of assays [...] Read more.
Ergosterol peroxide (EP) triggers apoptosis pathways by inducing reactive oxygen species (ROS) in TNBC cell lines. Excess ROS production is associated with major damage to mitochondria. We hypothesized that EP may act through ROS-induced mitochondrial dysfunction. Therefore, we performed a series of assays that assessed mitochondrial membrane potential (MMP), cellular respiration, and glycolysis in TNBC models. Cardiomyocytes derived from human-induced pluripotent stem cells were chosen as a non-cancerous model because of their high mitochondrial content. Two in vivo TNBC models were used to quantify the effect of EP on tumor volume and metastases. EP reduced MMP and disrupted mitochondrial functions exclusively in TNBC cells. In vivo EP was effective in reducing tumor volume without affecting liver function. There was also a significant decrease in metastasis to the lung, liver, and cancer stem cells following treatment. These results suggest EP is a promising therapy for TNBC. Full article
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapies)
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17 pages, 2902 KiB  
Article
CRISPR/Cas9 Targeting of Aldehyde Dehydrogenase 1A1 Reveals Heterogeneous Roles in Radiation Response and Redox Stress Across Clonal Lines in Triple-Negative Breast Cancer
by Grace O. Ajayi, Aihui Ma, Shirin R. Modarai, Lynn M. Opdenaker and Jennifer Sims-Mourtada
Int. J. Mol. Sci. 2025, 26(5), 2303; https://doi.org/10.3390/ijms26052303 - 5 Mar 2025
Viewed by 573
Abstract
The metabolic enzyme aldehyde dehydrogenase 1A1 (ALDH1A1), a cancer stem cell marker associated with poor outcomes in breast cancer, has emerged as a promising therapeutic target in TNBC. The aim of this study was to investigate the role of ALDH1A1 in radiation resistance [...] Read more.
The metabolic enzyme aldehyde dehydrogenase 1A1 (ALDH1A1), a cancer stem cell marker associated with poor outcomes in breast cancer, has emerged as a promising therapeutic target in TNBC. The aim of this study was to investigate the role of ALDH1A1 in radiation resistance and redox stress in triple negative breast cancer (TNBC). Functional knockouts of ALDH1A1 were generated by the CRISPR/Cas9-mediated deletion of ALDH1A1 in the SUM159 cell line, and three distinct clonal populations were isolated. Genetic targeting was confirmed by Sanger sequencing, and the loss of ALDH1A1 protein expression was validated by Western blotting. Functional assays assessed ALDEFLUOR activity, cell viability, self-renewal capacity, and reactive oxygen species (ROS) levels with or without radiation in both the bulk population and clonal lines. Interestingly, ALDEFLUOR activity was uniformly lost across all clonal lines; however, functional effects of ALDH1A1 loss on redox stress, survival, and radiation sensitivity were observed in only one clonal population. These findings highlight significant variability in the role of ALDH1A1 among clonal populations, reflecting the complexity of tumor heterogeneity. This underscores the importance of accounting for tumor heterogeneity when targeting ALDH1A1, as certain TNBC subpopulations may rely more heavily on ALDH1A1 function. These insights are critical for developing effective ALDH1A1-targeted therapies. Full article
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapies)
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20 pages, 2736 KiB  
Article
Dysregulated miRNA Expression and Androgen Receptor Loss in Racially Distinct Triple-Negative Breast Cancer
by Shristi Bhattarai, Bruna M. Sugita, Emanuelle Nunes-Souza, Aline S. Fonseca, Darshan Shimoga Chandrashekar, Mahak Bhargava, Luciane R. Cavalli and Ritu Aneja
Int. J. Mol. Sci. 2024, 25(24), 13679; https://doi.org/10.3390/ijms252413679 - 21 Dec 2024
Viewed by 796
Abstract
Androgen receptor (AR)-negative triple-negative breast cancer (TNBC), often termed quadruple-negative breast cancer (QNBC), disproportionately impacts women of African descent, leading to poorer overall survival (OS). MiRNAs regulate the expression of gene drivers involved in critical signaling pathways in TNBC, such as the AR [...] Read more.
Androgen receptor (AR)-negative triple-negative breast cancer (TNBC), often termed quadruple-negative breast cancer (QNBC), disproportionately impacts women of African descent, leading to poorer overall survival (OS). MiRNAs regulate the expression of gene drivers involved in critical signaling pathways in TNBC, such as the AR gene, and their expression varies across races and breast cancer subtypes. This study investigates whether differentially expressed miRNAs influence AR transcription, potentially contributing to the observed disparities between African American (AA) and European American (EA) QNBC patients. Race-annotated TNBC samples (n = 129) were analyzed for AR expression status and revealed the prevalence of QNBC in AA patients compared to EA (76.6% vs. 57.7%) and a significant association of AR loss with poor survival among AAs. The Cancer Genome Atlas (TCGA) RNA-seq data showed that AAs with TNBC (n = 32) had lower AR mRNA levels than EAs (n = 67). Among TCGA patients in the AR-low group, AAs had significantly poorer OS than EAs. In our cohort, 46 miRNAs exhibited differential expression between AAs and EAs with QNBC. Ten of these miRNAs (miR-1185-5p, miR-1305, miR-3161, miR-3690, miR-494-3p, miR-509-3-5p, miR-619-3p, miR-628-3p, miR-873-5p, and miR-877-5p) were predicted to target the AR gene/signaling. The loss of AR expression is linked to poorer prognoses in AA women. The understanding of the specific miRNAs involved and their regulatory mechanisms on AR expression could provide valuable insights into why AA women are more prone to QNBC. Full article
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapies)
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18 pages, 2967 KiB  
Article
Association of Computed Tomography Scan-Assessed Body Composition with Immune and PI3K/AKT Pathway Proteins in Distinct Breast Cancer Tumor Components
by Ting-Yuan David Cheng, Dongtao Ann Fu, Sara M. Falzarano, Runzhi Zhang, Susmita Datta, Weizhou Zhang, Angela R. Omilian, Livingstone Aduse-Poku, Jiang Bian, Jerome Irianto, Jaya Ruth Asirvatham and Martha Campbell-Thompson
Int. J. Mol. Sci. 2024, 25(24), 13428; https://doi.org/10.3390/ijms252413428 - 14 Dec 2024
Viewed by 1204
Abstract
This hypothesis-generating study aims to examine the extent to which computed tomography-assessed body composition phenotypes are associated with immune and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways in breast tumors. A total of 52 patients with newly diagnosed breast cancer were classified [...] Read more.
This hypothesis-generating study aims to examine the extent to which computed tomography-assessed body composition phenotypes are associated with immune and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways in breast tumors. A total of 52 patients with newly diagnosed breast cancer were classified into four body composition types: adequate (lowest two tertiles of total adipose tissue [TAT]) and highest two tertiles of total skeletal muscle [TSM] areas); high adiposity (highest tertile of TAT and highest two tertiles of TSM); low muscle (lowest tertile of TSM and lowest two tertiles of TAT); and high adiposity with low muscle (highest tertile of TAT and lowest tertile of TSM). Immune and PI3K/AKT pathway proteins were profiled in tumor epithelium and the leukocyte-enriched stromal microenvironment using GeoMx (NanoString). Linear mixed models were used to compare log2-transformed protein levels. Compared with the normal type, the low muscle type was associated with higher expression of INPP4B (log2-fold change = 1.14, p = 0.0003, false discovery rate = 0.028). Other significant associations included low muscle type with increased CTLA4 and decreased pan-AKT expression in tumor epithelium, and high adiposity with increased CD3, CD8, CD20, and CD45RO expression in stroma (p < 0.05; false discovery rate > 0.2). With confirmation, body composition can be associated with signaling pathways in distinct components of breast tumors, highlighting the potential utility of body composition in informing tumor biology and therapy efficacies. Full article
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapies)
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10 pages, 266 KiB  
Article
miRNAs in Signal Transduction of SMAD Proteins in Breast Cancer
by Tomasz Sirek, Agata Sirek, Przemysław Borawski, Nikola Zmarzły, Joanna Sułkowska, Katarzyna Król-Jatręga, Marcin Opławski, Dariusz Boroń, Michał Chalcarz, Piotr Ossowski, Konrad Dziobek, Damian Strojny, Kacper Boroń, Dominika Janiszewska-Bil and Beniamin Oskar Grabarek
Int. J. Mol. Sci. 2024, 25(18), 10088; https://doi.org/10.3390/ijms251810088 - 19 Sep 2024
Cited by 1 | Viewed by 1225
Abstract
The aim of this study was to identify miRNAs that could potentially influence the activity of SMAD proteins involved in TGFβ signal transduction in five types of breast cancer in Polish women. Patients with five breast cancer subtypes were included in the study: [...] Read more.
The aim of this study was to identify miRNAs that could potentially influence the activity of SMAD proteins involved in TGFβ signal transduction in five types of breast cancer in Polish women. Patients with five breast cancer subtypes were included in the study: luminal A (n = 130), luminal B HER2− (n = 100), luminal B HER2+ (n = 96), non-luminal HER2+ (n = 36), and TNBC (n = 43). During surgery, tumor tissue was removed along with a margin of healthy tissue (control). Molecular analysis included determination of the expression of genes related to SMAD protein signal transduction using mRNA microarrays and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression was determined using an enzyme-linked immunosorbent assay (ELISA). The miRNA profiling was performed using miRNA microarrays and the miRDB database. SMAD3 and SMAD5 were overexpressed in all types of breast cancer, which could be related to the reduced expression of miR-145, and the findings for SMAD4 and miR-155 were similar. Additionally, the level of SMAD7 was reduced, which may be due to the low activity of miR-15b and miR21b. This study determined the gene expression profiles involved in SMAD protein signal transduction across five different types of breast cancer and identified the miRNAs potentially regulating their activity. Overexpression of SMAD3, SMAD4, and SMAD5 suggests excessive activation of the TGFβ pathway, potentially promoting tumor growth and development. Concurrently, a significant reduction in SMAD7 expression removes inhibitory control in the TGFβ pathway, a phenomenon that is particularly evident in more aggressive breast cancer types. Full article
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapies)

Review

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27 pages, 1566 KiB  
Review
Facing the Challenge to Mimic Breast Cancer Heterogeneity: Established and Emerging Experimental Preclinical Models Integrated with Omics Technologies
by Alessia Ciringione and Federica Rizzi
Int. J. Mol. Sci. 2025, 26(10), 4572; https://doi.org/10.3390/ijms26104572 (registering DOI) - 10 May 2025
Abstract
Breast cancer (BC) is among the most common neoplasms globally and is the leading cause of cancer-related mortality in women. Despite significant advancements in prevention, early diagnosis, and treatment strategies made over the past two decades, breast cancer continues to pose a significant [...] Read more.
Breast cancer (BC) is among the most common neoplasms globally and is the leading cause of cancer-related mortality in women. Despite significant advancements in prevention, early diagnosis, and treatment strategies made over the past two decades, breast cancer continues to pose a significant global health challenge. One of the major obstacles in the clinical management of breast cancer patients is the high intertumoral and intratumoral heterogeneity that influences disease progression and therapeutic outcomes. The inability of preclinical experimental models to replicate this diversity has hindered the comprehensive understanding of BC pathogenesis and the development of new therapeutic strategies. An ideal experimental model must recapitulate every aspect of human BC to maintain the highest predictive validity. Therefore, a thorough understanding of each model’s inherent characteristics and limitations is essential to bridging the gap between basic research and translational medicine. In this context, omics technologies serve as powerful tools for establishing comparisons between experimental models and human tumors, which may help address BC heterogeneity and vulnerabilities. This review examines the BC models currently used in preclinical research, including cell lines, patient-derived organoids (PDOs), organ-on-chip technologies, carcinogen-induced mouse models, genetically engineered mouse models (GEMMs), and xenograft mouse models. We emphasize the advantages and disadvantages of each model and outline the most important applications of omics techniques to aid researchers in selecting the most relevant model to address their specific research questions. Full article
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapies)
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