bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–03–09
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes.
  2. Cancer-associated fibroblasts promote doxorubicin resistance in triple-negative breast cancer through enhancing ZFP64 histone lactylation to regulate ferroptosis.
  3. Inhibition of the MLL1-WDR5 interaction modulates epithelial to mesenchymal transition and metabolic pathways in triple-negative breast cancer cells.
  4. Bone marrow mesenchymal stem cells enrich breast cancer stem cell population via targeting metabolic pathways.
  5. Semaphorin 3F inhibits breast cancer metastasis by regulating the Akt-mTOR and TGFβ signaling pathways via neuropilin-2.
  6. Metabolic and transcriptional effects of bazedoxifene/conjugated estrogens in a model of obesity-associated breast cancer risk.
  7. Lipid metabolic reprograming: the unsung hero in breast cancer progression and tumor microenvironment.
  1. Mol Cancer Res. 2025 Mar 06.
    Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes.
    Yuhan Qiu, Andrew Chen, Rebecca Yu, Pablo Llevenes, Michael Seen, Naomi Y Ko, Stefano Monti, Gerald V Denis.
      Patients with triple negative breast cancer (TNBC) and comorbid Type 2 Diabetes (T2D), characterized by insulin resistance of adipose tissue, have higher risk of metastasis and shorter survival. Adipocytes are the main non-malignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology and mechanisms that couple T2D to TNBC outcomes are poorly understood. Here we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72h). EMT, proliferation and angiogenesis were elevated in IR vs. control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR- 145a-3p is highly differentially expressed between IS and IR, and potentially regulates metastasis. Implications: IR adipocyte exosomes modify the TME, enhance EMT, and promote brain metastasis-likely via miRNA pathways-suggesting that metabolic diseases like T2D foster a pro-metastatic TME, reducing survival, warranting close monitoring and potential metabolic interventions in TNBC patients with T2D.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-24-0494
  2. J Transl Med. 2025 Feb 28. 23(1): 247
    Cancer-associated fibroblasts promote doxorubicin resistance in triple-negative breast cancer through enhancing ZFP64 histone lactylation to regulate ferroptosis.
    KeJing Zhang, Lei Guo, Xin Li, Yu Hu, Na Luo.
       BACKGROUND: Cancer-associated fibroblasts (CAFs) have been identified to drive chemotherapy resistance in triple-negative breast cancer (TNBC). This study evaluated the functions of CAFs-mediated suppressive ferroptosis in doxorubicin (DOX) resistance in TNBC and its detailed molecular mechanisms.
    METHODS: TNBC cell lines were co-cultured with CAFs isolated from DOX-sensitive (CAF/S) or DOX-resistant (CAF/R) breast cancer tissues. Cell viability and death were assessed by cell counting Kit-8 (CCK-8) and propidium iodide (PI) staining. Ferroptosis was evaluated by detection of Fe2+, malondialdehyde (MDA), glutathione (GSH), and lipid reactive oxygen species (ROS) levels. Histone lactylation was determined by lactate production, pan-Kla and H3K18la expression. Molecular mechanism was determined by chromatin immunoprecipitation (ChIP) and dual luciferase reporter system. Molecule and protein expression was detected by quantitative Real-Time PCR (RT-qPCR), Western blotting, immunofluorescence and immunohistochemical staining. TNBC cells were injected into the mammary fat pad of nude mice to investigate DOX sensitivity in vivo.
    RESULTS: CAFs-derived lactate repressed ferroptosis to confer resistance of TNBC cells to DOX. Moreover, zinc finger protein 64 (ZFP64) expression was elevated in DOX-resistant TNBC and was associated with high histone lactylation level. CAFs facilitated histone lactylation to enhance ZFP64 expression, which triggered ferroptosis inhibition and DOX resistance. In addition, ZFP64 bound to the promoters of GTP cyclohydrolase-1 (GCH1) and ferritin heavy chain 1 (FTH1), thereby promoting their expression. Rescue experiments indicated that ZFP64 silencing-induced ferroptosis and high sensitivity of TNBC cells to DOX could be counteracted by GCH1 or FTH1 overexpression.
    CONCLUSION: CAFs acted as a ferroptosis inhibitor to cause DOX resistance of TNBC via histone lactylation-mediated ZFP64 up-regulation and subsequent promotion of GCH1-induced lipid peroxidation inhibition and FTH1-induced intracellular Fe2+ consumption.
    Keywords:  CAFs; DOX resistance; Ferroptosis; Histone lactylation; TNBC; ZFP64
    DOI:  https://doi.org/10.1186/s12967-025-06246-3
  3. Biochem Biophys Res Commun. 2025 Feb 28. pii: S0006-291X(25)00273-6. [Epub ahead of print]755 151559
    Inhibition of the MLL1-WDR5 interaction modulates epithelial to mesenchymal transition and metabolic pathways in triple-negative breast cancer cells.
    Shilpi Sarkar, Thirukumaran Kandasamy, Siddhartha Sankar Ghosh.
      Histone methylation is a key epigenetic modulation that regulates gene expression and is often associated with the pathogenesis of various cancers, including triple-negative breast cancer (TNBC). Histone methyltransferase, MLL1-WDR5 complex regulates gene transcription by catalyzing trimethylation of lysine 4 on histone H3 (H3K4me3) and promotes carcinogenesis. Herein, epithelial-to-mesenchymal transition (EMT) in TNBC cells is shown to facilitate upregulation of MLL1 and WDR5 expression by 4.7-fold and 3.84-fold, thereby establishing the association of these proteins in EMT dynamics. Therefore, we explored the therapeutic potential of inhibiting MLL1-WDR5 interaction using the small molecule inhibitor MM-102 in TNBC cell lines. MLL1 inhibition significantly reduced H3K4me3 levels and enhanced the apoptotic population by 30 % in MDA-MB-468 cells, demonstrating its cytotoxic potential. Notably, MM-102 treatment reverses the EMT process by upregulating the expression of epithelial markers (such as E-cadherin and claudin) and downregulating the expression of mesenchymal markers (such as β-catenin, Slug, caveolin 1, and fibronectin). In addition, MLL1 inhibition caused a metabolic shift, with a 5-fold increase in ALDO A and a 4-fold increase in ENO1 expression, indicating enhanced glycolysis. Further reduction in the fatty acid uptake and lipid droplet accumulation by MM-102 treatment signifies that targeting MLL1 also rewires the metabolic network in TNBC cells. Collectively, inhibiting MLL1 represents a promising therapeutic strategy for managing EMT-driven metastasis, reshaping metabolic reprogramming, and ultimately improving therapeutic outcomes in aggressive breast cancer.
    Keywords:  Epithelial to mesenchymal transition; Histone methylation; MLL1; Metabolic reprogramming; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151559
  4. Med Oncol. 2025 Mar 05. 42(4): 90
    Bone marrow mesenchymal stem cells enrich breast cancer stem cell population via targeting metabolic pathways.
    Zahra Ghanbari Movahed, Kamran Mansouri, Ali Hamrahi Mohsen, Maryam M Matin.
      The role of cancer cell metabolic reprogramming in the formation and maintenance of cancer stem cells (CSCs) has been well established. This reprogramming involves alterations in the metabolic pathways of cancer cells, leading to the acquisition of stem cell-like properties such as self-renewal and differentiation. This study aimed to investigate the potential effects of bone marrow mesenchymal stem cells (BM-MSCs) on the enrichment of breast CSCs. Exosomes (Exo) and conditioned media (CM) were isolated from BM-MSCs for use in this experimental study. The impact of BM-MSCs-Exo and BM-MSCs-CM on the expression of stemness genes NANOG and OCT-4, as well as CD24 and CD44 markers, was assessed in MCF-7 and MDA-MB-231 cell cultures to identify CSCs. Furthermore, the effects of BM-MSCs-Exo and BM-MSCs-CM on cancer cell metabolism were evaluated by examining changes in glycolysis, the pentose phosphate pathway (PPP), and amino acid profiles. Additionally, the influence of BM-MSCs-Exo and BM-MSCs-CM on tumor growth in vivo was also investigated. The analysis of stemness marker expression in cells treated with BM-MSCs-Exo and BM-MSCs-CM revealed an increase in stemness characteristics compared to the control group. Furthermore, the examination of changes in cell metabolism following these treatments showed alterations in glycolysis, PPP, and amino acid metabolism pathways. Additionally, it was demonstrated that BM-MSCs-Exo and BM-MSCs-CM can promote tumor growth in mice following transplantation of 4T1 cells. These findings suggest that BM-MSCs-Exo and BM-MSCs-CM can enrich the population of CSCs in MCF-7 and MDA-MB-231 cells by targeting metabolic pathways, however, further studies are required to elicit the exact mechanisms of these phenomena.
    Keywords:  BM-MSCs; Breast cancer cells; Cancer stem cells; Conditioned media; Exosomes; Metabolism
    DOI:  https://doi.org/10.1007/s12032-025-02632-5
  5. Sci Rep. 2025 Mar 03. 15(1): 7394
    Semaphorin 3F inhibits breast cancer metastasis by regulating the Akt-mTOR and TGFβ signaling pathways via neuropilin-2.
    Hironao Nakayama, Akari Murakami, Hisayo Nishida-Fukuda, Shinji Fukuda, Erina Matsugi, Masako Nakahara, Chiaki Kusumoto, Yoshiaki Kamei, Shigeki Higashiyama.
      Class 3 semaphorins are axon guidance factors implicated in tumor and vascular biology, including invasive activity. Recent studies indicate that semaphorin 3F (SEMA3F) is a potent inhibitor of metastasis; however, its functional role in breast cancer is not fully understood. We found that exogenous SEMA3F inhibited phosphorylation of Akt and mTOR downstream kinase S6K in MDA-MB-231 and MCF7 cells via neuropilin-2 (NRP2) receptor. We also examined the effect of SEMA3F on breast cancer progression in vivo allograft model. The mouse 4T1 breast cancer cells or 4T1 cells overexpressing SEMA3F (4T1-SEMA3F) were implanted into mammary fat pads of Balb/c mice. We found that tumor growth was significantly inhibited in 4T1-SEMA3F injected mice compared to controls. Immunostaining revealed a remarkable reduction in the expression of vimentin, a mesenchymal cell marker, in 4T1-SEMA3F tumors. We also observed that mice injected with 4T1-SEMA3F cells had minimal metastasis to the liver and lungs, compared to controls. As a novel feature, SEMA3F suppressed TGFβ-induced Smad2 phosphorylation, resulting in the inhibition of cell invasiveness and epithelial-to-mesenchymal transition (EMT) in breast cancer. Consistently, a significant correlation between reduced expression of SEMA3F and poor outcome in patients with breast cancer. We conclude that SEMA3F acts as a dual inhibitor of the Akt-mTOR and TGFβ signaling pathways; thus, it has the potential to treat metastatic breast cancer.
    Keywords:  Breast cancer; Metastasis; Neuropilin-2; Semaphorin 3F
    DOI:  https://doi.org/10.1038/s41598-025-91559-y
  6. JCI Insight. 2025 Mar 06. pii: e182694. [Epub ahead of print]
    Metabolic and transcriptional effects of bazedoxifene/conjugated estrogens in a model of obesity-associated breast cancer risk.
    Erin D Giles, Katherine L Cook, Ramsey M Jenschke, Karen A Corleto, Danilo Landrock, Tara N Mahmood, Katherine E Sanchez, Alina Levin, Stephen D Hursting, Bruce F Kimler, Barry S Komm, Carol J Fabian.
      Many risk-eligible women refuse tamoxifen for primary prevention of breast cancer due to concerns about common side effects such as vasomotor symptoms. Tamoxifen may also induce or worsen insulin resistance and hypertriglyceridemia, especially in women with obesity. Bazedoxifene/conjugated estrogens (BZA/CE) reduces vasomotor symptoms and is currently undergoing evaluation for breast cancer risk reduction. However, the impact of BZA/CE on insulin resistance and metabolic health, particularly in those with excess adiposity, is understudied. Here, we examined the effects of obesity on response to BZA/CE in a rat model of breast cancer risk using older ovary-intact rats. Female Wistar rats received carcinogen to increase mammary cancer risk and were fed a high-fat diet to promote obesity. Lean and obese rats were selected based on adiposity, then randomized to BZA/CE or vehicle for 8 weeks. BZA/CE reduced adiposity, enriched small (insulin-sensitive) mammary adipocytes, increased the abundance of beneficial metabolic gut microbes (Faecalbaculum rodentium and Odoribacter laneus), and reversed obesity-associated changes in lipids and adipokines. BZA/CE also reversed obesity-induced mammary enrichment of cell proliferation pathways, consistent with risk-reducing effects. Together, these data support the use of BZA/CE to improve metabolic health and reduce breast cancer risk in individuals with obesity.
    Keywords:  Adipose tissue; Breast cancer; Metabolism; Obesity; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.182694
  7. Mol Cancer. 2025 Mar 03. 24(1): 61
    Lipid metabolic reprograming: the unsung hero in breast cancer progression and tumor microenvironment.
    Mengting Wan, Shuaikang Pan, Benjie Shan, Haizhou Diao, Hongwei Jin, Ziqi Wang, Wei Wang, Shuya Han, Wan Liu, Jiaying He, Zihan Zheng, Yueyin Pan, Xinghua Han, Jinguo Zhang.
      Aberrant lipid metabolism is a well-recognized hallmark of cancer. Notably, breast cancer (BC) arises from a lipid-rich microenvironment and depends significantly on lipid metabolic reprogramming to fulfill its developmental requirements. In this review, we revisit the pivotal role of lipid metabolism in BC, underscoring its impact on the progression and tumor microenvironment. Firstly, we delineate the overall landscape of lipid metabolism in BC, highlighting its roles in tumor progression and patient prognosis. Given that lipids can also act as signaling molecules, we next describe the lipid signaling exchanges between BC cells and other cellular components in the tumor microenvironment. Additionally, we summarize the therapeutic potential of targeting lipid metabolism from the aspects of lipid metabolism processes, lipid-related transcription factors and immunotherapy in BC. Finally, we discuss the possibilities and problems associated with clinical applications of lipid‑targeted therapy in BC, and propose new research directions with advances in spatiotemporal multi-omics.
    Keywords:  Breast cancer; Cancer progression; Lipid metabolism; Metabolism-based therapies; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-025-02258-1
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