bims-merabr 2026-10-04 papers

Front Oncol. 2026 ;16 1848165

Lipid metabolism reprogramming: key mechanism of breast cancer endocrine therapy resistance.

Zhiqi Sui, Xiaoxi Han, Shaochun Liu, Yuhan Tang, Han Zhang, Linlin Fan, Chang Su, Wenhui Zhao.

ER+ (estrogen receptor positive) breast cancer is the most common subtype of breast cancer, for which endocrine therapy is the primary treatment. However, the development of drug resistance severely limits the clinical efficacy. In recent years, lipid metabolism reprogramming, as a key metabolic feature of tumor cells adapting to microenvironmental stress and driving progression and metastasis, has gained increasing attention due to its role in promoting endocrine therapy resistance. This review focuses on the lipid metabolism reprogramming that occurs in ER+ breast cancer cells in response to endocrine therapy, systematically elaborating on the key molecular mechanism changes in fatty acid synthesis, cholesterol metabolism, lipid droplet homeostasis, and mitochondrial fatty acid β-oxidation. These metabolic remodeling processes not only provide survival advantages and energy to drug-resistant cells but also directly promote the formation and development of drug-resistant phenotypes by affecting signal transduction and epigenetic regulation pathways. By integrating the latest research progress in this field, this article aims to deeply reveal the intrinsic connection between lipid metabolism reprogramming and endocrine resistance, providing important theoretical basis and direction for overcoming the bottleneck of drug resistance and developing new combination therapy strategies targeting lipid metabolism.

Keywords: ER+ breast cancer; endocrine therapy resistance; fatty acid synthesis; fatty acid β-oxidation; lipid metabolic reprogramming

DOI: https://doi.org/10.3389/fonc.2026.1848165

J Clin Invest. 2026 Oct 01. pii: e205415. [Epub ahead of print]136(19):

HIF-1-mediated PPME1 expression promotes breast cancer progression via AKT activation and β-catenin recruitment.

Yajing Lyu, Varen Talwar, Yongkang Yang, Si-Sim Kang, Shuyi Li, Shaima Salman, Daiana Drehmer, Yufeng Wang, Chelsey Chen, Vijay Ramu, Sujin Kim, Dylan Park, Tina Yi-Ting Huang, Emmanuel Datan, Dominic Dordai, Jonathan P Schneck, Gregg L Semenza.

Hypoxia-inducible factor 1 (HIF-1) orchestrates the transcriptional regulation of thousands of genes involved in breast cancer (BC) progression. Here, we identified protein phosphatase 2A (PP2A) methylesterase 1 (PPME1) as a critical HIF-1 target gene that drives oncogenic signaling under hypoxic conditions. In BC cells, HIF-1-dependent PPME1 expression caused inhibition of the PP2A catalytic subunit (PP2Ac), thereby diminishing PP2A activity, which led to AKT activation, phosphorylation of β-catenin, and its nuclear translocation. Nuclear β-catenin cooperates with HIF-1 to promote BC stem cell specification by activating transcription of the NANOG and KLF4 genes, which encode pluripotency factors, and to drive immune evasion by activating transcription of VEGFA, which recruits and polarizes immunosuppressive tumor-associated macrophages and ISG20, which represses STAT1/IRF1-dependent expression of CXCL10, thereby impairing CD8+ T cell recruitment. In vivo, PPME1 knockdown altered the tumor immune microenvironment, enhanced antitumor immunity, and synergized with anti-CTLA-4 immunotherapy to enable complete tumor eradication. These findings establish PPME1 as a critical regulator linking hypoxia signaling, stemness, and immune evasion and highlight its potential as a BC therapeutic target in combination with immune checkpoint blockade.

Keywords: Breast cancer; Genetics; Oncology

DOI: https://doi.org/10.1172/JCI205415

bioRxiv. 2026 Sep 24. pii: 2026.09.23.752387. [Epub ahead of print]

Metabolic-epigenetic coupling between leucine catabolism and glycolysis drives CDK4/6 inhibitor resistance.

Michael Uj Oliphant, Klarisa Norton, Kiran Kurmi, Howard Yang, Shakchhi Joshi, Jonah Lee, Nina Kozlova, Taru Muranen, John G Clohessy, Marcia Haigis, Senthil K Muthuswamy.

Resistance to CDK4/6 inhibitors limits the durability of therapy for ER+ breast cancer. Despite the identification of mechanisms that regulate resistance, the metabolic adaptations that enable therapeutic escape remain poorly understood. Here, we identify a metabolic-epigenetic circuit that drives resistance by coordinately rewiring amino acid and glucose metabolism. CDK4/6 inhibitor-resistant ER+ tumor cells upregulate the leucine transporter SLC7A5, enhancing leucine uptake. SLC7A5 overexpression is sufficient to confer palbociclib resistance across ER+ cell lines, patient-derived organoids and xenografts. Stable isotope tracing in cell lines and in xenograft tumors revealed that leucine is catabolized through BCAT2 and HMGCL to increase acetyl-CoA levels, and elevated acetyl-CoA promotes H3K27 acetylation at the GLUT1 promoter, upregulating GLUT1 expression and glycolytic activity. Disrupting leucine transport, catabolism, or availability suppresses GLUT1 expression and restores therapeutic sensitivity in resistant models. In patients receiving palbociclib-based therapy, high SLC7A5 expression and coordinated SLC7A5-GLUT1 co-expression are associated with shorter progression-free survival. Together, these findings define a metabolic- epigenetic mechanism linking branched-chain amino acid catabolism to glycolysis and identify a biomarker-associated metabolic vulnerability in advanced ER+ breast cancer.
Statement of Significance: Resistance to CDK4/6 inhibitors is nearly universal in ER+ breast cancer. We identify a metabolic- epigenetic circuit in which acetyl-coA derived from leucine catabolism promotes epigenetic changes at the GLUT1 promoter, thereby increasing glucose uptake and driving glycolysis. Disrupting leucine transport, catabolism, or availability suppresses this program and restores drug sensitivity, identifying crosstalk between amino acid metabolism and glycolysis in regulating drug resistance. High expression of the leucine transporter, SLC7A5, is associated with shorter progression-free survival, revealing a biomarker-associated metabolic vulnerability.

DOI: https://doi.org/10.64898/2026.09.23.752387

bioRxiv. 2026 Sep 08. pii: 2026.09.04.749413. [Epub ahead of print]

Targeting fibroblast activation suppresses chemotherapy-induced pro-invasive remodeling of the extracellular matrix.

Anna Yui, Liyi Peng, Katie C Lew, Dylan J Landau, Crystal Zhang, Thomas J Gerton, Marissa Li, Steffy Jullian Guyard, Mallory M Caron, Jackson P Fatherree, Rachel A McGinn, Abraham L Bayer, Pilar Alcaide, Charlotte Kuperwasser, Madeleine J Oudin.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that accounts for nearly 20% of breast cancer diagnoses. Despite recent approvals of novel therapeutic agents for TNBC, neoadjuvant chemotherapy remains part of standard of care treatment for TNBC patients. However, approximately 60% of TNBC patients who received neoadjuvant chemotherapy fail to achieve pathological complete response and face significantly elevated risks of recurrence and distant metastasis. We have shown that chemotherapy can induce significant changes in TNBC tumor extracellular matrix (ECM) that drive tumor cell invasion and may contribute to recurrence. Here, we investigate how chemotherapy drugs can impact resident fibroblasts, the major generators of ECM in the breast tissue. We find that chemotherapy activates fibroblasts and that doxorubicin specifically induces the production of pro-invasive ECM by fibroblasts via TGF-β/Smad3 signaling. An FDA-approved tyrosine kinase inhibitor nintedanib suppressed doxorubicin-induced fibroblast activation and pro-invasive ECM production by fibroblasts in vitro . Additionally, in a TNBC mouse model, nintedanib reduced fibroblast activation markers in tumors, suppressed tumor cell motility in the tumor ECM, and reduced lung metastasis. These findings demonstrate a novel mechanism by which chemotherapy can induce fibroblast activation and imply that targeting fibroblast activation reduces chemotherapy-induced metastasis in TNBC.

DOI: https://doi.org/10.64898/2026.09.04.749413

Cancer Res. 2026 Oct 02.

EZH2 Inhibition Induces a Metabolic Stress Response Sensitizing Triple-Negative Breast Cancer to Glutaminase Targeting.

Lucas Porras, Marina Carrière, Ann-Sophie Gironne, Hugo Philippeau, Gabriel Alzial, Elise Quadri, Jeanne Cormery, Yousef Alaessa, Anie Monast, Faustine Gorse, Myriame St-Arnaud, Mariana De Sa Tavares Russo, Sylvie Nathalie Christine Mader, Daina Z Avizonis, Sébastien Lemieux, Morag Park, Geneviève Deblois.

EZH2, the catalytic subunit of the histone methyltransferase complex PRC2, is overexpressed and associated with poor prognosis in triple-negative breast cancer (TNBC). Although EZH2 inhibition significantly alters chromatin landscapes and gene expression, it has limited impact on the growth of TNBC models, suggesting adaptive compensatory mechanisms. Here, we demonstrated that EZH2 inhibition causes the accumulation of misfolded proteins and double-stranded RNA (dsRNA), triggering an essential integrated stress response (ISR) through PKR and PERK activation. By inducing ISR-mediated ATF4, EZH2 inhibition enhanced amino acid flux and promoted glutaminolysis to support TNBC cell survival. Pharmacological targeting of this metabolic axis with a glutaminase inhibitor in combination with EZH2 inhibition significantly impaired TNBC cell proliferation and tumor growth. These findings reveal a stress-driven metabolic adaptation that sustains TNBC survival upon EZH2 blockade and highlight inhibition of this pathway as a strategy to enhance the efficacy of EZH2 inhibitors in TNBC.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0801