bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–05–10
ten papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. The Endocrine Disrupting Compounds Bisphenol-A and α-Zeranol Mimic the Estrogen Transcriptional Program to Promote Proliferation and Stemness in Breast Cancer Cells.
  2. Extracellular vesicles from hypertrophic cardiomyocytes promote breast cancer progression.
  3. Hematopoietic Stem Cell Tropism Mediated Targeting of Breast Cancer Stem Cells via Alteration of Tumor Immune-Microenvironment.
  4. Antiproliferative effects of TUBB3 in ERα-positive postmenopausal breast cancer model cells.
  5. Bone marrow B cell collapse promotes bone metastasis in breast cancer.
  6. Glucose metabolic reprogramming: a novel strategy to enhance radiotherapy response to triple-negative breast cancer.
  7. Runx1 and Runx2 act in concert to suppress Wnt/β-catenin-driven mammary tumourigenesis.
  8. Cancer-associated adipocyte promote progression and immunosuppression in triple-negative breast cancer.
  9. YKT6 promotes breast cancer progression and is associated with poor prognosis and immune infiltration.
  10. The role of pluripotency regulators in triple-negative breast cancer immune response.
  1. Mol Carcinog. 2026 May 03.
    The Endocrine Disrupting Compounds Bisphenol-A and α-Zeranol Mimic the Estrogen Transcriptional Program to Promote Proliferation and Stemness in Breast Cancer Cells.
    Cassandra Winz, Eric Li, Caroline Xie, Kyo Chang Lee, Kevin Boguszewski, Shlok Rohatagi, Rita Hahn, Ray Rancourt, Philip Furmanski, Nanjoo Suh.
      Excessive activation of the estrogen receptor (ER) drives proliferation, progression, and the formation of breast cancer stem cells (CSCs) in ER-positive breast cancer. Estrogenic endocrine disrupting compounds (EDCs) found in plastics, water, and food are also able to bind to the ER. Thus, we hypothesized that estrogenic EDCs mimic estrogen (E2) in the pathogenesis of breast cancer by promoting their survival and proliferation. Three estrogenic EDCs routinely found in human biosamples were selected for analysis: bisphenol-A (BPA), diethyl-hexyl phthalate (DEHP), and alpha-zeranol (αZAL). We assessed proliferation, transcriptional reprogramming, and CSC formation in breast cancer cell lines. E2, BPA, and αZAL significantly increased cell proliferation in ER-positive, but not ER-negative cell lines. This was reversed after administration of the ER-antagonist, ICI 182,780. BPA and αZAL upregulated estrogen target genes (PGR, TFF1) and increased levels of cell-cycle protein. RNA sequencing analysis revealed that BPA and αZAL altered expression of genes related to cell division, DNA repair, and estrogen signaling, with a substantial transcriptional overlap between EDCs and estrogen treatments. Additionally, BPA and αZAL increased the proportion of CSCs, defined as the CD24low/CD44high expressing subpopulation. Overall, these data indicate that BPA and αZAL act as functional estrogen mimics in breast cancer cells, activating canonical estrogen signaling pathways and promoting stem-like characteristics. Notably, this study provides the first transcriptomic and stem-associated characterization of αZAL in ER-positive breast cancer cells, revealing a robust estrogenic mode of action. This work provides mechanistic insight into how environmental EDCs may influence ER-positive breast cancer biology.
    Keywords:  breast cancer; cancer stem cells; endocrine disrupting compounds; estrogen
    DOI:  https://doi.org/10.1002/mc.70127
  2. Commun Biol. 2026 May 06.
    Extracellular vesicles from hypertrophic cardiomyocytes promote breast cancer progression.
    Weiwei Chen, Yutong Yao, Benkai Xin, Peipei An, Yonghao Dai, Hanwei Gao, Jingtong Yang, Xiaoyu Wang, Yueru Shi, Zhoulei Zhu, Nan Zhang, Youzhong Wan, Yuquan He, Xin Hu.
      Several cardiovascular diseases are associated with tumor development. But the mechanisms underlying how the hypertrophic heart promotes tumor progression remain unknown. Here, we show that extracellular vesicles from hypertrophic cardiomyocytes facilitate cancer progression. Following transverse aortic constriction to induce cardiac hypertrophy, 4T1-Luc cells are orthotopically implanted into mice. Concurrently, AC16 cells are treated with angiotensin II, and extracellular vesicles isolated from these cells are administered to BALB/c nude mice previously implanted with MDA-MB-231 cells in their mammary fat pads. Both transverse aortic constriction-operated mice and mice receiving extracellular vesicles from angiotensin II-treated AC16 cells exhibit accelerated breast cancer progression; however, treatment with GW4869, an extracellular-vesicles-release inhibitor, suppresses this effect. Transcriptome sequencing and mass spectrometry indicate that the expression of miR-362-5p, S100A7, and S100A8 is upregulated in these extracellular vesicles, which significantly boosts breast cancer cell proliferation, invasion, and migration. Importantly, miR-362-5p, S100A7, and S100A8 levels are elevated in plasma extracellular vesicles from patients with myocardial hypertrophy and are positively correlated with inflammatory indices. Our research identifies the specific factors in hypertrophic cardiomyocytes that drive tumor progression, laying a theoretical foundation for future targeted intervention and prevention.
    DOI:  https://doi.org/10.1038/s42003-026-10104-3
  3. J Cell Physiol. 2026 May;241(5): e70179
    Hematopoietic Stem Cell Tropism Mediated Targeting of Breast Cancer Stem Cells via Alteration of Tumor Immune-Microenvironment.
    Sumit Mallick, Siddhartha Biswas, Sudheer Shenoy P, Bipasha Bose.
      The ontogenic development of hematopoietic stem cells (HSCs) occurs across diverse niches, with HSCs migrating from the aorta-gonad-mesonephros (AGM) to the fetal liver and finally residing in the bone marrow after birth, where adult HSCs replenish the hematopoietic system. The HSC niche critically regulates tropism and proliferation via factors secreted by the microenvironment interaction. Here, we hypothesized that HSCs display tropism toward the aggressive cancer stem cell (CSC) niches of triple-negative breast cancer (TNBC) and MCF-7 cells breast cancer, which exhibit high relapse rates and are potential targets for cell therapy. Our results demonstrate HSC-specific tropism toward breast CSCs, leading to interactions that trigger HSC differentiation into CD4+ and CD8+ subpopulations within the cancer microenvironment. Proteomics of migrated HSCs toward TNBC-CSCs/MCF-7 cells revealed significant upregulation of IL-7, Notch, and other proteins involved in T cell activation and migration pathways. Metabolomics of HSC-conditioned medium (HSC-CM)-treated CSCs/MCF-7 cells further demonstrated that HSC-CM arrests TNBC-CSC growth and cell cycle progression by altering the mitochondrial bioenergetics. This study highlights the potential of leveraging both HSCs and HSC-derived factors for personalized therapies targeting CSCs in TNBC.
    Keywords:  Methodology and formal analysis; conditioned media; hematopoietic stem cells; metabolomics; mitochondrial bioenergetics; proteomics; trans differentiation; triple negative breast cancer stem cells; tumor microenvironment; tumor tropism
    DOI:  https://doi.org/10.1002/jcp.70179
  4. Biochem Biophys Res Commun. 2026 Apr 27. pii: S0006-291X(26)00600-5. [Epub ahead of print]821 153836
    Antiproliferative effects of TUBB3 in ERα-positive postmenopausal breast cancer model cells.
    Masayo Hirao-Suzuki, Koki Kanameda, Shuso Takeda.
      Long-term estrogen-deprived (LTED) cells were obtained from parental MCF-7 breast cancer (BC) cells cultured under conditions of prolonged estrogen deprivation. In LTED cells, which mimic estrogen receptor α (ERα)-positive BC that has relapsed after endocrine therapy, βIII-tubulin (TUBB3) expression is downregulated. However, the biological significance of TUBB3 downregulation is unclear. To address this, we assessed the effects of siRNAs targeting individual TUBB isotypes. Among of them, only TUBB3-targeting siRNA stimulated the proliferation of MCF-7 cells, but it did not affect LTED cells. After treating LTED cells with 17β-estradiol (E2), the upregulation of TUBB3 expression and antiproliferative effects were detected, suggesting that TUBB3 mediates the antiproliferative effects of E2. Furthermore, the attenuated TUBB3 expression was related to poor prognosis in patients with ERα-positive BC receiving endocrine therapy. These findings identify TUBB3 as an E2-sensitive antiproliferative molecule in ERα-positive BC cells, suggesting that it could be targeted for endocrine therapy-resistant BC.
    Keywords:  Aromatase inhibitor resistance; Endocrine therapy; Estrogen receptor α; LTED cells; Postmenopausal breast cancer; TUBB3
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153836
  5. bioRxiv. 2026 Apr 24. pii: 2026.04.21.720007. [Epub ahead of print]
    Bone marrow B cell collapse promotes bone metastasis in breast cancer.
    Ana Teijeiro, Claudia A Rivera, Motoyoshi Nagai, Adam X Miranda, Eduard Ansaldo, Paula Juliana Perez-Chaparro, Bianca M Nagata, Derron A Alves, Niki M Moutsopoulos, Yasmine Belkaid.
      Metastasis remains the primary cause of cancer-related deaths and is characterized by complex reprogramming of systemic processes. Emerging evidence indicates that extraosseous tumors can rewire bone marrow physiology and disrupt hematopoiesis, thereby compromising effective systemic immune responses. However, how tumor-induced immune alterations in bone marrow contribute to skeletal metastasis remains poorly defined. Here, using immunocompetent mouse models of mammary tumor bone metastasis, we show that mammary cancer cells precondition the bone marrow niche prior to metastatic colonization, driving early remodeling of the microenvironment and depleting bone marrow lymphoid populations. Specifically, cancer cells induce a dramatic B cell reduction, the most abundant lymphoid subset in bone marrow, resulting from dysregulated cell cycle gene expression in pre-B cells, along with impaired B-cell proliferation and differentiation. These findings are further validated in breast cancer bone metastasis patients, who exhibit significant bone marrow B-cell loss alongside disrupted molecular and developmental programs. A causal role for B cells in restraining skeletal metastasis is supported by the finding that experimental B-cell depletion significantly increases both incidence and severity of bone metastasis. Mechanistically, we find that B-cell loss is driven by systemic elevation of G-CSF. Accordingly, pharmacological neutralization of G-CSF significantly reduces both B-cell depletion and bone metastasis susceptibility. Collectively, our data reveal that breast cancer cells can distantly hijack B-cell developmental trajectories, promoting skeletal metastasis. This work identifies B cells and G-CSF as potential therapeutic targets in bone metastasis and highlights the importance of targeting early bone marrow immune dysregulation to prevent or limit skeletal metastasis.
    HIGHLIGHTS: Mammary tumor cells reshape the bone marrow niche inducing B cell lossBone marrow B cell development is impaired in mammary tumor metastasisExperimental depletion of B cells promotes bone metastasisG-CSF mediates B cell loss in mammary tumor metastasis.
    DOI:  https://doi.org/10.64898/2026.04.21.720007
  6. Front Public Health. 2026 ;14 1715716
    Glucose metabolic reprogramming: a novel strategy to enhance radiotherapy response to triple-negative breast cancer.
    Lu Gan, Qian Li, Boyi Yu, Jing Si, Qiang Li, Weiqiang Chen, Bing Wang.
      Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor prognosis and limited responsiveness to conventional therapies. Increasing evidence shows that the reprogramming of glucose metabolism is a hallmark of cancer cells, supporting their rapid proliferation, metastatic potential, and therapy resistance. This metabolic shift is particularly pronounced in TNBC, where reliance on glycolysis is greater than in other breast cancer subtypes. Consequently, strategies that target glucose metabolic pathways may offer a promising means to overcome treatment resistance and improve clinical outcomes. In this review, we summarize the unique features and regulatory mechanisms of glycolytic reprogramming in TNBC, with attention to tumor heterogeneity and its implications for disease progression and treatment response. We highlight recent preclinical studies that evaluate therapeutic approaches designed to exploit metabolic vulnerabilities, including glycolysis inhibition, metabolic enzyme targeting, and combination regimens with radiotherapy. Collectively, these findings suggest that interventions aimed at glycolytic pathways hold considerable potential to enhance radiosensitivity in TNBC. We discuss the translational prospects of this research, emphasizing the value of glycolysis-related genes as predictive biomarkers and as foundations for the development of novel targeted agents. While preliminary evidence is encouraging, further validation is required to establish the safety, efficacy, and clinical applicability of these strategies in human patients. Continued research in this area is expected to contribute to the development of more effective therapeutic options, ultimately improving the management and prognosis of TNBC.
    Keywords:  biomarker; glucose metabolic reprogramming; radiosensitivity; radiotherapy; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fpubh.2026.1715716
  7. Br J Cancer. 2026 May 07.
    Runx1 and Runx2 act in concert to suppress Wnt/β-catenin-driven mammary tumourigenesis.
    Alessandra I Riggio, Kerri Sweeney, Robin Shaw, Amy Lawlor, Adiba Khan, Nicola Ferrari, Jayanthi Anand, Laura Ca Galbraith, Kathryn Gilroy, Courtney Bull, Alex L Young, Dimitris Athineos, Holly Hall, Farah Ghaffar, Mark Hughes, Claire A Mitchell, Louise Mitchell, Colin Nixon, Peter D Adams, Edward W Roberts, Crispin J Miller, Philip D Dunne, Kirsteen J Campbell, Ewan R Cameron, Karen Blyth.
       INTRODUCTION: The genes encoding RUNX1 and its binding partner CBFβ are recurrently reported to be mutated in breast cancer, a major cause of mortality in women worldwide. However, the functional role for these proteins remains unproven.
    METHODS: The putative tumour suppressor role of Runx1 was investigated in genetic mouse models of breast cancer. Stem cell assays, immunohistochemistry and RNAseq analyses were applied to study biological and molecular mechanisms.
    RESULTS: Runx1 loss of function leads to accelerated disease onset and tumour development in breast cancer models. Combined deletion of Runx1 and Runx2 further resulted in mammary cells becoming exquisitely sensitive to WNT-driven transformation, with expedited emergence of multiple tumours. Runx1 ablation induces a stem cell-like phenotype in mammary epithelial cells, whilst transcriptomic analysis demonstrated activation of multiple oncogenic pathways, especially when Runx2 was co-deleted. Altered Runx expression in the mammary epithelium also drove alterations in the tumour immune microenvironment, with changes to neutrophil and macrophage populations.
    CONCLUSIONS: Runx1 restricts some forms of breast cancer and inhibits the full oncogenic potential of aberrant WNT signalling. Combined Runx1 and Runx2 loss dramatically accelerates disease progression suggesting that Runx2 can substitute for Runx1 in dampening the oncogenic effects of WNT signalling.
    DOI:  https://doi.org/10.1038/s41416-026-03439-5
  8. Front Oncol. 2026 ;16 1797152
    Cancer-associated adipocyte promote progression and immunosuppression in triple-negative breast cancer.
    Xichao Zhang, Shenjie Zhong, Shan Liu, Xiaofeng Mu, Gang Chen, Wen Chen.
      Triple-negative breast cancer (TNBC) is characterized by highmetastatic potential and a lack of effective targeted therapies. Within the tumor microenvironment (TME) of TNBC, adipocyte can undergo transformation into cancer-associated adipocytes (CAA) through interactions with cancer cells; however, the specific role in the progress of TNBC is still not well described. This study aimed to investigate the impact of CAA on the malignant behavior of TNBC and its underlying mechanisms. CAA model was successfully established by co-culturing 3T3-L1-induced adipocytes with 4T1 cells, which exhibited characteristic features such as reduced lipid accumulation. Functional assays demonstrated that co-culture with CAA significantly enhanced the migration and invasion capabilities of 4T1 cells. In vivo experiments showed that co-injection of CAA with tumor cells accelerated primary tumor growth and promoted lung metastasis in mice. Mechanistic analysis revealed that in tumor tissues coexisting with CAA, E-cadherin expression was downregulated, accompanied by increased Ki67 expression and activation of the PI3K/AKT signaling pathway. Furthermore, CAA induces an immunosuppressive TME, characterized by elevated PD-L1 expression and reduced CD8+T cell infiltration. In conclusion, this study demonstrates that CAA promotes TNBC progression by activating epithelial-mesenchymal transition (EMT) and the PI3K/AKT pathway, as well as remodeling an immunosuppressive microenvironment, providing experimental insight into tumor-adipocyte interactions and identifying potential therapeutic targets.
    Keywords:  cancer-associated adipocyte; epithelial-mesenchymal; immunosuppressive microenvironment; transition; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1797152
  9. Front Immunol. 2026 ;17 1742661
    YKT6 promotes breast cancer progression and is associated with poor prognosis and immune infiltration.
    Meilin Zhang, Jingjing Yuan, Yaxuan Liu, Yiran Qiu, Mingdi Zhang, Hongliang Chen.
       Background: YKT6 is markedly overexpressed across multiple tumor types and plays a role in driving their progression. However, the correlation between YKT6 and breast cancer remains poorly understood. Therefore, we aimed to investigate the potential prognostic value and biological function of YKT6 gene in breast cancer.
    Methods: Public datasets, clinic sample and tissue microarray (TMA) were used for YKT6 expression and prognostic value analyses. The relevance between YKT6 expression, tumor-immune infiltrates and tumor mutation burden (TMB) was examined using the TCGA database. Cellular functional assays were performed to verify the biological behavior of YKT6 in breast cancer cells. Moreover, transcriptome sequencing (RNA-seq) was conducted to explore the underlying mechanism of YKT6.
    Results: YKT6 was significantly upregulated in breast cancer tissue comparing to normal tissue(P<0.05) and higher YKT6 expression was significantly linked to worse clinical prognosis, advanced tumor stages, and distant metastasis(P<0.05). Additionally, YKT6 expression is correlated with the infiltration of various immune cell and TMB. Knockdown of YKT6 impaired the proliferation, invasion, and migration abilities of breast cancer cells, and increased apoptosis. Functional enrichment analysis revealed that YKT6 primarily influenced breast cancer progression through the cell cycle, as well as biological processes such as autophagy, apoptosis, and ferroptosis. Moreover, knockdown of YKT6 suppressed the activity of mTORC1.
    Conclusion: YKT6 may serve as a potential prognostic biomarker for breast cancer. The expression level of YKT6 was correlated with tumor-infiltrating immune cells in breast cancer. It may offer potential value for the treatment of breast cancer patients.
    Keywords:  YKT6; bioinformatics; biomarker; breast cancer; immune infiltration; prognosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1742661
  10. Front Genet. 2026 ;17 1771872
    The role of pluripotency regulators in triple-negative breast cancer immune response.
    Carolina López-Santana, Fabio Mendez-Rivera, David A Bernal-Estévez.
      Triple-negative breast cancer (TNBC) is defined by the absence of estrogen, progesterone, and HER2 receptor expression. A critical challenge in managing TNBC is its high concentration of cancer stem cells (CSCs), which drives chemotherapy resistance and correlates with poor patient survival. In normal physiology, stem cell pluripotency and differentiation are governed by core transcription factors (such as Oct4, Sox2, Nanog, Klf4, and c-Myc) alongside key signaling networks, including the Notch, Wnt/β-catenin, and Sonic Hedgehog (Shh) pathways. During carcinogenesis, aberrant activation of these regulators in TNBC not only promotes the self-renewal of tumor cells but also actively facilitates immune evasion. Specifically, overexpressed pluripotency transcription factors enable cancer cells to downregulate antigen presentation molecules (e.g., MHC class I) and secrete immunomodulatory cytokines. Concurrently, dysregulated signaling, such as the Wnt/β-catenin pathway, inhibits dendritic cell maturation and recruits Myeloid-Derived Suppressor Cells (MDSCs) and regulatory T cells (Tregs) into the tumor microenvironment, thereby blunting the anti-tumor T cell response. This review examines the role of key pluripotency regulators in TNBC-mediated immune evasion, highlighting emerging immunotherapeutic strategies targeting these networks and summarizing current clinical research.
    Keywords:  breast cancer stem cells; immune response; pluripotency regulators; transcription factors; triple negative breast cancer
    DOI:  https://doi.org/10.3389/fgene.2026.1771872
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