2026-04-14T03:29:48Zhttps://recercat.cat/oai/request
oai:recercat.cat:10256/207982024-06-18T12:41:45Zcom_2072_452955com_2072_2054col_2072_453079
RECERCAT author Menéndez Menéndez, Javier Abel author Mehmi, Inderjit author Papadimitropoulou, Adriana author Van der Steen, Travis author Cuyàs, Elisabet author Verdura, Sara author Espinoza, Ingrid author Vellon, Luciano author Atlas, Ella author Lupu, Ruth 2024-06-18T12:41:45Z 2024-06-18T12:41:45Z 2020-10-14 http://hdl.handle.net/10256/20798 HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2- breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Tamoxifèn Tamoxifen Medicaments antineoplàstics Antineoplastic agents Mama -- Càncer -- Tractament Breast -- Cancer -- Treatment Mama -- Càncer -- Aspectes endocrins Breast -- Cancer -- Endocrine aspects Fatty Acid Synthase is a key enabler for endocrine resistance in Heregulin-overexpressing Luminal B-like breast cancer info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion peer-reviewed