{"doi":"10.1210/endocr/bqaf168","title":"Androgen Receptors Promote Oxidative Phosphorylation and Resistance to Palmitate Lipotoxicity in ER-Mutant Breast Cancer","abstract":"Aromatase inhibitors (AI) are first-line therapy for postmenopausal women with estrogen receptor-expressing (ER+) breast cancer (BC). AI therapy effectively reduces recurrence and extends lifespan for patients with ER+ BC through long-term estrogen deprivation (LTED) resulting from inhibition of the enzyme aromatase that converts androgens to estrogens. However, up to 50% of ER+ BC recurs as AI-resistant metastatic disease within 10 years of diagnosis. AI-resistant BC upregulates androgen receptors (AR) and mitochondrial oxidative phosphorylation (OXPHOS) and requires OXPHOS and fatty acid oxidation (FAO). The liver and lung, common ER+ BC metastatic sites, have high abundance of the saturated fatty acid palmitate. We asked whether AR signaling regulates OXPHOS in the context of LTED. Using mutant ER-expressing MCF7 and T47D BC cell lines with AR antagonism via the anti-androgen enzalutamide and with shRNA knockdown, we demonstrate that AR supports cell growth, OXPHOS, FAO, and resistance to palmitate lipotoxicity. We identify AR as a positive regulator of the carnitine acyltransferase family enzyme CRAT that promotes OXPHOS capacity. These studies identify AR as pro-tumor in the LTED setting and as a therapeutic target for ER-mutant BC that develops under the selective pressure of AI therapy.","journal":"Endocrinology","year":2025,"id":527487,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9492,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":816844,"name":"Dillon P. Boulton","orcid":"0000-0002-7781-3101","position":1,"is_corresponding":false},{"id":319595,"name":"Nicole S. Spoelstra","orcid":"0009-0003-3981-5960","position":2,"is_corresponding":false},{"id":258002,"name":"M. Cecilia Caino","orcid":"0000-0001-8294-8070","position":3,"is_corresponding":false},{"id":236061,"name":"Min Yu","orcid":"0000-0002-3969-8720","position":4,"is_corresponding":false},{"id":10973,"name":"Andrew Goodspeed","orcid":"0000-0001-7055-7128","position":5,"is_corresponding":false},{"id":272248,"name":"Jennifer K. Richer","orcid":"0000-0002-9960-0991","position":6,"is_corresponding":false},{"id":865807,"name":"Dane Sessions","orcid":"0000-0002-9754-2791","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41216931","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}