bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–08–03
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Immune infiltration related PRDX4 facilitates the malignant features and drug resistance of breast cancer.
  2. COL4A2 drives ECM remodeling and stiffness increasing to promote breast cancer metastasis via YAP signaling pathway in dECM induced models.
  3. Estrogen receptor α regulates SVCT2 protein level in human breast cancer cells.
  4. SIX1 transmits signals for breast cancer progression via the ZEB1/IL6/STAT3 signaling axis.
  5. Key players in the breast cancer microenvironment: From fibroblasts to immune cells.
  6. Long-Chain Fatty Acids Alter Estrogen Receptor Expression in Breast Cancer Cells.
  7. HER2-Driven Breast Cancer: Role of the Chaperonin HSP90 in Modulating Response to Trastuzumab-Based Therapeutic Combinations.
  1. Sci Rep. 2025 Jul 28. 15(1): 27507
    Immune infiltration related PRDX4 facilitates the malignant features and drug resistance of breast cancer.
    Wenying Jiang, Maonan Wang, Qingning Chen, Xiaoqian Yu, Guoqian Liu, Xiaoyun He, Cheng Mei, Chunlin Ou.
      The incidence of breast cancer continues to increase annually, posing a significant challenge for countries worldwide in terms of its prevention and treatment. Therefore, identifying novel therapeutic targets for breast cancer is urgently needed. The peroxiredoxin (PRDX) family is regarded as a good diagnostic marker for various tumors. However, the expression and prognostic significance of PRDX family members in breast cancer remain unclear and require systematic investigation. By using bioinformatic tools such as UALCAN, TIMER2.0, Human Protein Atlas Project (HPA), Gene Set Cancer Analysis (GSCA), and the cBioportal database, we systematically analyzed the expression pattern, prognostic value, methylation status and immune infiltrating association of PRDX gene family members in breast cancer. Through comprehensive analysis, we found that PRDX4 has good prognostic value and is closely related to immune infiltration, and further exploration of its oncogenic function in breast cancer is warranted. Subsequently, we performed a series of cellular assays to explore the potential role of PRDX4 in the progression of breast cancer. We demonstrated that PRDX4 promoted the proliferation, invasion, metastasis, and inhibited the apoptosis of breast cancer cells. In addition, PRDX4 expression was associated with the half maximal inhibitory concentration (IC50) of neratinib which primarily targets human epidermal growth factor receptor 2 (HER2) and showed good binding in molecular docking. Our subsequent experiments showed that the PRDX4-HER2 axis may serve as a potential combined target for neratinib therapy. Our findings suggest that PRDX4 may be a potential diagnostic and prognostic marker for breast cancer, and targeting PRDX4 could represent a novel strategy to improve the efficacy of targeted therapy for patients with HER2-positive breast cancer.
    Keywords:  Breast cancer; Drug resistance; Immune infiltration; PRDX4; Prognosis; Therapeutic target
    DOI:  https://doi.org/10.1038/s41598-025-13361-0
  2. Biomater Adv. 2025 Jul 22. pii: S2772-9508(25)00257-2. [Epub ahead of print]177 214430
    COL4A2 drives ECM remodeling and stiffness increasing to promote breast cancer metastasis via YAP signaling pathway in dECM induced models.
    Jing Peng, Weilai Zhu, Chi Zhang, Shuishui Yin, Jie Ye, Haijiao Mao, Mei Li, Jiyuan Zhao.
      Mechanical stress significantly increases during tumor progression. Accumulated research focuses on mechanical transduction, due to the great therapeutic difficulties brought by the mechanical changes. Extracellular matrix (ECM) serves as the key tissue microenvironment providing mechanical cues for tumor cells. However, the mechanism of tumor ECM assembly, stiffness and the resulting cellular mechanical response were rarely reported. Here, decellularized ECM (dECM) models from low-metastatic and metastatic breast cancer tissues via in situ tumor implantation of mammary fat pad in immunodeficient mice were generated to simulate the tumor microenvironment. Wavy fiber structure, finer fibers, but higher stiffness were revealed in the metastatic dECM. Elevated expression of type IV collagen (COL IV) was correlated with the enhanced cell migration and the higher ECM stiffness due to the increased crosslinking of collagen fibers. Further analysis identified COL4A2 (a subunit of COLIV) as a key protein involved in this process. Virus infection of tumor cells led to a decrease in COL4A2 specificity in the dECM in situ, accompanied by the decreased ECM stiffness, the inhibition of cell migration in vitro, and the reduction of metastasis in vivo. Additionally, the increased ECM stiffness caused by the high content of COL4A2 in dECM scaffolds activated YAP1 expression, which might be a potential mechanism. Therefore, the promotion of the stiffness in the basement membrane by COL4A2 via collagen fiber cross-linking might be a key mechanical target for breast cancer metastasis. The targeting ECM mechanics could offer a new strategy to inhibit tumor progression.
    Keywords:  Breast cancer; COL4A2; Collagen stiffness; Decellularized extracellular matrix (dECM); Metastasis
    DOI:  https://doi.org/10.1016/j.bioadv.2025.214430
  3. Sci Rep. 2025 Jul 29. 15(1): 27629
    Estrogen receptor α regulates SVCT2 protein level in human breast cancer cells.
    Soon Young Jang, Eunbi Hong, Yebin Jo, Jiyun Kim, Jong-Ho Kim, Yuran Na, Chang-Hwan Yeom, Yoon Jung Yang, Emanuela Jacchetti, Manuela Teresa Raimondi, Seyeon Park.
      The solute carrier (SLC) protein family, traditionally recognized for transporting molecules across cell membranes, is gaining attention for its broader roles, including signaling. Among SLC proteins, the ascorbate transporter SVCT2 remains poorly understood, particularly in relation to estrogen receptor alpha (ERα), a key regulator in breast cancer cells. Here, we investigate how ERα regulates SVCT2 and its implications for chemoresistance. Our results demonstrate that ERα knockdown significantly reduces SVCT2 protein levels, impairing cellular ascorbic acid uptake. Mechanistically, ERα directly interacts with SVCT2. We show that X-linked inhibitor of apoptosis protein (XIAP), an E3 ubiquitin ligase, targets SVCT2 for ubiquitination and subsequent proteasomal degradation in ERα-deficient conditions. Notably, silencing XIAP restored SVCT2 stability, underscoring its regulatory role. Functionally, ERα or SVCT2 knockdown decreases doxorubicin-induced cytotoxicity, accompanied by increased expression of ATP-binding cassette (ABC) transporter genes, which mediate drug efflux and contribute to chemoresistance. These findings uncover a novel regulatory axis between ERα and SVCT2, mediated by XIAP, and establish SVCT2 as a critical factor in maintaining cellular ascorbic acid levels and drug sensitivity. Targeting XIAP or modulating SVCT2 may represent promising therapeutic strategies for overcoming resistance in ERα-positive breast cancer. This study advances our understanding of the interplay between nutrient transport and cancer therapy, offering new avenues for intervention.
    Keywords:  Breast cancer; Degradation; Drug resistance; Estrogen receptor alpha; SVCT2; XIAP
    DOI:  https://doi.org/10.1038/s41598-025-11758-5
  4. Oncogene. 2025 Jul 26.
    SIX1 transmits signals for breast cancer progression via the ZEB1/IL6/STAT3 signaling axis.
    Liantao Guo, Yan Rao, Yawen Song, Jiawei Hu, Zixuan Luo, Shengrong Sun, Chuang Chen, Deguang Kong.
      Epithelial-mesenchymal transition (EMT) and breast cancer stem cells (BCSCs) are pivotal in breast cancer mechanism research. It was demonstrated that Sine oculis homeobox homolog 1 (SIX1) orchestrates breast cancer EMT and BCSCs, concurrently activating the Signal transducer and activator of transcription 3 (STAT3) signaling pathway. Yet, the mechanism by which SIX1 modulates STAT3 and its potential to regulate EMT and BCSCs through STAT3 signaling remain unexplored. Here, cellular, animal, organoid models, and integrated single-cell transcriptomic and ST-seq of human breast cancer specimens were conducted. The results revealed that SIX1 can enhance Zinc finger E-box binding homeobox 1 (ZEB1) expression and translation, which in turn binds to the Interleukin-6 (IL6) promoter (1138bp-1148bp) to stimulate its transcription, translation, and secretion. Subsequently, IL6 can activate the cell's own STAT3 signaling pathway, promote the phosphorylation of STAT3, promote the downstream signal c-Myc and Cyclin D1 transduction, and promote the expression of stem cell-related transcription factors such as ALDH1A1, OCT4, and SOX2, thereby promoting EMT and stemness. In addition, this study found a new cell interaction model, in which the above-mentioned secreted IL6 can promote the activation of STAT3 signaling pathway, EMT and stemness transformation in the surrounding cells with low expression of SIX1 in a paracrine manner. Our data favored that SIX1/ZEB1/IL6 axis activated the STAT3 signaling pathway of the breast cells themselves and surrounding cells with low SIX1 expression, thus promoting EMT and stemness transformation, activating the malignant progression of the whole breast cancer.
    DOI:  https://doi.org/10.1038/s41388-025-03499-6
  5. World J Clin Oncol. 2025 Jul 24. 16(7): 107339
    Key players in the breast cancer microenvironment: From fibroblasts to immune cells.
    Sacide Çakal, Buket Er Urgancı, Selda Şimşek.
      Breast cancer is one of the most common malignancies worldwide and is a major cause of cancer-related mortality among women. Beyond tumor cells, the tumor microenvironment (TME) also plays an important role in cancer progression, therapy resistance, and metastasis. The TME is a complex ecosystem consisting of stromal and immune cells, extracellular matrix (ECM), and various signaling molecules that dynamically interact with tumor cells. Cancer-associated fibroblasts remodel the ECM and secrete growth factors that promote tumor growth and invasion. Immune cells, such as tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, often contribute to an immunosuppressive environment that hinders anti-tumor immune responses. The ECM provides structural support and acts as a reservoir for signaling molecules that influence cancer cell behavior. These components evolve together with tumor cells, facilitating immune evasion, therapy resistance, and epithelial-to-mesenchymal transition, which promotes metastasis. Understanding these interactions is necessary to develop novel therapeutic strategies that target both tumor and microenvironmental components. This minireview highlights the key stromal and immune elements within the breast cancer microenvironment, discussing their individual and collective roles in tumor progression and clinical outcomes, while emphasizing emerging therapeutic approaches aiming to reprogram the TME to improve treatment efficacy.
    Keywords:  Breast cancer; Cancer-associated fibroblasts; Cytokines; Epithelial-to-mesenchymal transition; Extracellular matrix; Metastasis; Targeted therapy; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.5306/wjco.v16.i7.107339
  6. Int J Mol Sci. 2025 Jul 13. pii: 6722. [Epub ahead of print]26(14):
    Long-Chain Fatty Acids Alter Estrogen Receptor Expression in Breast Cancer Cells.
    Ruiko Ogata, Yi Luo, Rina Fujiwara-Tani, Rika Sasaki, Ayaka Ikemoto, Kaho Maehana, Ayaka Sasaki, Takamitsu Sasaki, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu.
      Long-chain fatty acids (LCFAs) have emerged as important regulators of cancer metabolism, but their impact on hormone receptor expression in breast cancer (BCA) remains poorly understood. In this study, we investigated the effects of five LCFAs-linoleic acid (LA), oleic acid (OA), elaidic acid (EA), palmitic acid (PA), and α-linolenic acid (LNA)-on two BCA cell lines: luminal-type MCF7 and triple-negative MDA-MB-231 (MB231). All LCFAs suppressed cell viability and mitochondrial function in a dose-dependent manner, accompanied by decreased membrane potential, increased reactive oxygen species production, and a metabolic shift. Notably, OA reduced both mRNA and nuclear protein levels of estrogen receptor alpha (ERα) in MCF7 cells, leading to impaired responses to estradiol and tamoxifen. In contrast, PA induced nuclear ERα expression in MB231 cells, although ER signaling remained inactive. MicroRNA profiling revealed that OA upregulated ER-suppressive miR-22 and miR-221 in MCF7, while PA increased miR-34a in MB231, contributing to ERα induction. These findings suggest that specific LCFAs modulate ER expression through epigenetic and post-transcriptional mechanisms, altering hormonal responsiveness in BCA. Our results offer new insights into how dietary lipids may influence therapeutic efficacy and tumor behavior by regulating nuclear receptor signaling.
    Keywords:  breast cancer; estrogen receptor; long-chain fatty acid; triple negative breast cancer
    DOI:  https://doi.org/10.3390/ijms26146722
  7. Int J Mol Sci. 2025 Jul 09. pii: 6593. [Epub ahead of print]26(14):
    HER2-Driven Breast Cancer: Role of the Chaperonin HSP90 in Modulating Response to Trastuzumab-Based Therapeutic Combinations.
    Italia Falcone, Elena Giontella, Stefano Giuliani, Giulia Borghesani, Alessandro Valenti, Valentina Zambonin, Sara Monteverdi, Luisa Carbognin, Emilio Bria, Ludovica Ciuffreda, Fabiana Conciatori, Chiara Bazzichetto, Serena Pedron, Alessia Nottegar, Sara Zanelli, Alice Muzzarelli, Alessandra Fabi, Silvia Migliaccio, Elisabetta Ferretti, Roberto Bei, Elena Fiorio, Maurizio Fanciulli, Isabella Sperduti, Anna Caliò, Michele Milella.
      Mechanistic relationships between heat shock protein 90 (HSP90) and human epidermal growth factor receptor 2 (HER2) are complex and clinical correlations in breast cancer remain inconsistent. We investigated the role of HSP90 expression in the response of breast cancer cells to HER2-targeted treatments, by measuring cell viability/proliferation and protein expression after genetic and pharmacologic HER2/HSP90 modulation. HSP90 expression was also assessed by immunohistochemistry in a series of 72 metastatic, HER2+ breast cancer patients. In HER2+ breast cancer models (AU565, BT474, MCF7-HER2), HER2 downregulation induced HSP90 upregulation and growth inhibitory synergism between trastuzumab and docetaxel. HSP90 downregulation blunted the response to trastuzumab and docetaxel and their synergistic interactions. The addition of pertuzumab caused little additional growth inhibition, but HSP90 silencing unmasked a synergistic growth inhibitory effect with the triple combination. Conversely, HSP90 downregulation blunted the therapeutic response to trastuzumab/pertuzumab/tamoxifen or trastuzumab-emtansine. In HER2+ breast cancer patients, high HSP90 expression was associated with significant progression-free survival benefit with the triple combination, as compared with trastuzumab and chemotherapy, although the interaction test was not statistically significant. Overall, our results highlight a mechanistic role for HSP90 in determining the response of breast cancer cells to HER2-targeted agents and suggest that trastuzumab/pertuzumab combinations may be particularly advantageous in HSP90-high, HER2+ breast cancer.
    Keywords:  HER2; HSP90; breast cancer; combination treatments; predictive biomarker; therapeutic strategies
    DOI:  https://doi.org/10.3390/ijms26146593
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