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oai:recercat.cat:10256/207922024-06-18T12:41:41Zcom_2072_452955com_2072_2054col_2072_453079

Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer Menéndez Menéndez, Javier Abel Papadimitropoulou, Adriana Van der Steen, Travis Cuyàs, Elisabet Oza-Gajera, Bharvi P. Verdura, Sara Espinoza, Ingrid Vellon, Luciano Mehmi, Inderjit Lupu, Ruth Mama -- Càncer -- Tractament Breast -- Cancer -- Treatment Mama -- Càncer -- Aspectes endocrins Breast -- Cancer -- Endocrine aspects Estrògens -- Receptors Estrogen -- Receptors Tamoxifèn Tamoxifen Medicaments antineoplàstics Antineoplastic agents The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity-an in vitro metric of tumorigenicity-of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas 2021-03-06 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion peer-reviewed http://hdl.handle.net/10256/20792 http://hdl.handle.net/10256/20792 eng info:eu-repo/semantics/altIdentifier/doi/10.3390/cancers13051132 info:eu-repo/semantics/altIdentifier/issn/2072-6694 info:eu-repo/semantics/altIdentifier/eissn/2072-6694 Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf MDPI (Multidisciplinary Digital Publishing Institute) Cancers, 2021, vol. 13, num. 5, p. 1132 Articles publicats (IdIBGi) Menéndez Menéndez, Javier Abel Papadimitropoulou, Adriana Steen, Travis Vander Cuyàs, Elisabet Oza-Gajera, Bharvi P. Verdura, Sara Espinoza, Ingrid Vellon, Luciano Mehmi, Inderjit Lupu, Ruth 2021 Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer Cancers 13 5 1132