bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–08–10
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Lean breast adipocytes secrete an oxylipin that suppresses breast cancer via ferroptosis.
  2. Endocrine therapy induces oxidative stress in ER+ breast cancer that sensitizes persister cells to ferroptosis.
  3. MACL-1 Breast Cancer Secretome Reprograms Fibroblasts to Enhance Inflammation and Tumor Progression.
  4. Emerging mechanisms of therapy resistance in metastatic ER+ breast cancer.
  5. Distinct lipidomic profiles in breast cancer cell lines relate to proliferation and EMT phenotypes.
  6. Triple-Negative Breast Cancer Cells Activate Sensory Neurons via TRPV1 to Drive Nerve Outgrowth and Tumor Progression.
  7. Aging-induced semaphorin 7a promotes TGF-β1-mediated cell plasticity and breast tumor metastases.
  1. bioRxiv. 2025 Jul 21. pii: 2025.07.17.665258. [Epub ahead of print]
    Lean breast adipocytes secrete an oxylipin that suppresses breast cancer via ferroptosis.
    Meghan C Curtin, Abigail E Jackson, Elisabeth A Brown, J Alan Maschek, David Lum, James E Cox, Alana L Welm, Keren I Hilgendorf.
      Obesity is predicted to become the largest modifiable risk factor for breast cancer in postmenopausal women, yet the mechanisms underlying this association are unclear. We identified a novel role for the endogenous oxylipin 9S-HODE, secreted by lean adipocytes, to induce ferroptosis in breast cancer cells while sparing normal breast epithelial cells. Obese adipocytes fail to secrete 9S-HODE, suggesting that the loss of ferroptosis induction significantly contributes to the acceleration of obesity-associated breast cancer. Consequently, the inhibition of ferroptosis accelerates breast cancer in lean, but not obese, mice. Further, 9S-HODE inhibits the growth of patient-derived breast cancer organoids, and supplementing 9S-HODE into tumors in obese mice is sufficient to reduce tumor burden, underscoring its potential as a therapeutic agent.
    DOI:  https://doi.org/10.1101/2025.07.17.665258
  2. bioRxiv. 2025 Jul 23. pii: 2025.07.18.665614. [Epub ahead of print]
    Endocrine therapy induces oxidative stress in ER+ breast cancer that sensitizes persister cells to ferroptosis.
    Steven Tau, Malone Friedman, Alyssa M Roberts, Lauren R Ferridge, Sierra A Kleist, Lauren Cressey, Arminja N Kettenbach, Christopher J Shoemaker, Todd W Miller.
      Despite endocrine therapy, recurrence and progression of estrogen receptor alpha (ER)-positive breast cancer remain significant clinical problems. We therefore sought to identify mechanisms underlying endocrine-tolerant persistence. Endocrine-tolerant persister ER+ breast cancer cells were oxidatively stressed during endocrine therapy. Proteomic analysis revealed upregulation of antioxidant-driving enzymes including glutathione peroxidase 4 (GPX4) in persisters. Relief of oxidative stress enhanced persister fitness. The increased oxidative state of persisters enabled lipid peroxidation and ferroptosis. Persisters had an altered lipidome with increased levels of polyunsaturated fatty acids prone to peroxidation, which was attributable in part to increased lysophosphatidylcholine acyltyransferase 3 (LPCAT3, MBOAT5) expression via loss of ER-mediated repression during endocrine therapy. Treatment with the GPX4 inhibitor RSL3 enhanced the anti-persister effects of endocrine-based therapies in xenograft-bearing mice. These findings supporting the development of therapeutic strategies to leverage the oxidative stress induced by endocrine-based therapies and drive ferroptosis as a treatment for ER+ breast cancer.
    Statement of Significance: Endocrine therapy increases oxidative stress and sensitizes endocrine-tolerant persister ER+ breast cancer cells to ferroptosis, indicating that therapies targeting this metabolic dependency could help prevent disease recurrence and progression.
    DOI:  https://doi.org/10.1101/2025.07.18.665614
  3. An Acad Bras Cienc. 2025 ;pii: S0001-37652025000300605. [Epub ahead of print]97(3): e20250146
    MACL-1 Breast Cancer Secretome Reprograms Fibroblasts to Enhance Inflammation and Tumor Progression.
    Rodrigo Junio R Barros, Andreia Laura P Rodrigues, Camila Dourado, Luciana Maria Silva, Jonas Enrique A Perales, Sandra Lauton-Santos, Andreia Barroso, Jader S Cruz.
      Tumor-secreted factors reprogram the stromal microenvironment to facilitate cancer progression. This study investigates the effects of the MACL-1 breast cancer cell secretome on CCD19-Lu fibroblasts. Fibroblasts treated with the MACL-1 secretome exhibited increased proliferation, altered morphology, and upregulated expression of vimentin, NFκB, and fibroblast-activating protein, indicative of an inflammatory, activated phenotype. Additionally, elevated mitochondrial superoxide levels and an enrichment of proteases were detected in the secretome, but not in corresponding cell lysates. These findings suggest that the MACL-1 secretome promotes fibroblast activation and inflammation, underscoring its potential role in tumor-stroma interactions and breast cancer progression.
    DOI:  https://doi.org/10.1590/0001-3765202520250146
  4. Endocrinology. 2025 Aug 04. pii: bqaf127. [Epub ahead of print]
    Emerging mechanisms of therapy resistance in metastatic ER+ breast cancer.
    Thu H Truong, Natasha I Roman Ortiz, Chinasa A Ufondu, Su-Jeong Lee, Julie H Ostrander.
      Breast cancer is the most frequently diagnosed cancer in women with over 316,000 new cases expected to be diagnosed in 2025. Nearly 80% of new breast cancer cases will be estrogen receptor-positive (ER+). While ER+ breast cancer has a high 5-year survival rate, patients are at risk of developing late recurrence and metastasis for 10 to 20 years after initial diagnosis. Late recurrence and metastasis are associated with therapy resistance and disease progression. Understanding the molecular mechanisms that drive therapy resistance and disease progression is essential for the development of therapies that will prevent and treat advanced ER+ breast cancer. This review will focus on mechanisms of therapy resistance associated with standard treatments for advanced ER+ breast cancer, including CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR pathway inhibitors. Additionally, we will highlight how therapy resistance enriches for breast cancer stem-like populations and how targeting this population of cells may be advantageous for preventing breast cancer progression.
    Keywords:  Breast cancer; CDK4/6; Cancer stem-like cells; estrogen receptor; therapy resistance
    DOI:  https://doi.org/10.1210/endocr/bqaf127
  5. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Aug 03. pii: S1388-1981(25)00087-3. [Epub ahead of print] 159679
    Distinct lipidomic profiles in breast cancer cell lines relate to proliferation and EMT phenotypes.
    Hanneke Leegwater, Zhengzheng Zhang, Xiaobing Zhang, Xuesong Wang, Thomas Hankemeier, Annelien J M Zweemer, Bob van de Water, Erik Danen, Menno Hoekstra, Amy C Harms, Alida Kindt, Sylvia E Le Dévédec.
      Rewiring of lipid metabolism is a hallmark of cancer, supporting tumor growth, survival, and therapy resistance. However, lipid metabolic heterogeneity in breast cancer remains poorly understood. In this study, we systematically profiled the lipidome of 52 breast cancer cell lines using liquid chromatography-mass spectrometry to uncover lipidomic signatures associated with tumor subtype, proliferation, and epithelial-to-mesenchymal (EMT) state. A total of 806 lipid species were identified and quantified across 21 lipid classes. The main lipidomic heterogeneity was associated with the EMT state, with lower sphingolipid, phosphatidylinositol and phosphatidylethanolamine levels and higher cholesterol ester levels in aggressive mesenchymal-like cell lines compared to epithelial-like cell lines. In addition, cell lines with higher proliferation rates had lower levels of sphingomyelins and polyunsaturated fatty acid (PUFA) side chains in phospholipids. Next, changes in the lipidome over time were analyzed for three fast-proliferating mesenchymal-like cell lines MDA-MB-231, Hs578T, and HCC38. Triglycerides decreased over time, leading to a reduction in lipid droplet levels, and especially PUFA-containing triglycerides and -phospholipids decreased during proliferation. These findings underscore the role of EMT in metabolic plasticity and highlight proliferation-associated lipid dependencies that may be exploited for therapeutic intervention. In conclusion, our study reveals that EMT-driven metabolic reprogramming is a key factor in lipid heterogeneity in breast cancer, providing new insights into tumor lipid metabolism and potential metabolic vulnerabilities.
    Keywords:  Breast cancer; Cancer metabolism; Cell line panels; Epithelial to mesenchymal transition; Lipidomics
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159679
  6. bioRxiv. 2025 Jul 26. pii: 2025.07.22.666151. [Epub ahead of print]
    Triple-Negative Breast Cancer Cells Activate Sensory Neurons via TRPV1 to Drive Nerve Outgrowth and Tumor Progression.
    Hanan Bloomer, Savannah R Parker, Audrey L Pierce, Wesley Clawson, Mallory M Caron, Thomas Gerton, Ankit Pandey, Thanh T Le, Tolulope Adewumi, Charlotte Kuperwasser, Michael Levin, Madeleine J Oudin.
      The tumor microenvironment in triple-negative breast cancer (TNBC) is characterized by increased sensory nerve density, which contributes to cancer progression by promoting migration and metastasis. However, the origin of tumor-innervating nerves and the mechanisms driving sensory innervation into tumors remain poorly understood. Using in vivo retrograde labeling techniques, we show that mammary tumors are associated with an increase in nerves originating from the dorsal root ganglia. Additionally, we find that TNBC cells trigger stress and activation markers and induce neuronal firing in a transient receptor potential anilloid subtype 1 (TRPV1)-dependent manner. In both 2D and 3D cell culture models, TNBC cells promote outgrowth of sensory nerves that is abrogated with Trpv1 knockout. We identified c-Jun and IL-6 as an effector of neurite outgrowth that acts downstream of TRPV1 to promote outgrowth in vitro . Finally, in Trpv1 knockout mice, TNBC tumors exhibit delayed growth and reduced lung metastasis. These findings suggest that a critical role for TRPV1 in tumor-nerve crosstalk, offering a potential target to reduce metastatic disease.
    DOI:  https://doi.org/10.1101/2025.07.22.666151
  7. Cell Rep. 2025 Aug 01. pii: S2211-1247(25)00813-7. [Epub ahead of print]44(8): 116042
    Aging-induced semaphorin 7a promotes TGF-β1-mediated cell plasticity and breast tumor metastases.
    Kelsey T Kines, Heather R Fairchild, Alan M Elder, Lauren M Cozzens, Zachary P Strugar, Veronica M Wessells, Alexandria R Becks, Weston W Porter, Virginia F Borges, Traci R Lyons.
      Breast cancer risk is transiently increased in postpartum women, and this risk is prolonged in women whose first childbirth occurs after age 30. We observe elevated semaphorin 7a (SEMA7A) in tumor tissues from patients with breast cancer aged 31-39 diagnosed <10 years after childbirth. In the aged normal murine mammary gland, transforming growth factor β+ (TGF-β+) cells have increased levels of surface SEAM7A compared to the young. TGF-β1 induces SEMA7A expression in non-transformed mammary epithelial and breast cancer cells via multiple mechanisms. In mouse mammary tumor models, we observe accelerated tumor growth and metastases, increased TGF-β+SEMA7A+ cells, and epithelial-to-mesenchymal plasticity in aged mice. SEMA7A knockout and heterozygous littermates reveal that these phenotypes depend on SEMA7A in the host. We further show SEMA7A's pro-metastatic phenotype and abrogate it via a function-blocking antibody. Collectively, these results highlight the impact aging has on the mammary gland and the risk for breast cancer tumorigenesis.
    Keywords:  CP: Cancer; EMT; SEMA7A; TGF-β; aging; breast cancer; epithelial-mesenchymal plasticity; metastasis; postpartum breast cancer
    DOI:  https://doi.org/10.1016/j.celrep.2025.116042
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