{"doi":"10.1016/j.jbc.2025.110405","title":"HSD3B1 upregulation via LRH1 sustains estrogen receptor signaling and promotes endocrine resistance in breast cancer","abstract":"Endocrine resistance is a major challenge in the treatment of estrogen receptor-positive (ER + ) breast cancer, often leading to disease recurrence and metastasis. 3β-Hydroxysteroid dehydrogenase 1 (3βHSD1, encoded by HSD3B1 ) catalyzes the rate-limiting conversion of dehydroepiandrosterone (DHEA) to androstenedione (AD), the major substrate for aromatase and a key precursor for estrogen biosynthesis. However, the regulation of HSD3B1 in endocrine-resistant breast cancer remains unclear. We show that long-term estrogen deprivation (LTED) or tamoxifen treatment induces HSD3B1 expression and enzymatic activity, sustaining DHEA metabolism and ER signaling in resistant ER + breast cancer cells. T47D-LTED and T47D-4OHT cells exhibited increased HSD3B1 expression and enhanced DHEA metabolism. HSD3B1 deficiency impaired DHEA-driven survival, confirming its role in endocrine resistance. Mechanistically, we identify liver receptor homolog-1 (LRH1/NR5A2) as a key transcriptional regulator of HSD3B1 . LRH1 inhibition suppressed HSD3B1 expression, DHEA metabolism, and ER target gene activation, demonstrating its role in sustaining estrogen synthesis and tumor adaptation. Our findings establish HSD3B1 as a critical mediator of endocrine resistance and identify LRH1 as an upstream regulator. Targeting HSD3B1 or LRH1 may offer a new therapeutic strategy to restore endocrine sensitivity in ER + breast cancer.","journal":"Journal of Biological Chemistry","year":2025,"id":526028,"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":0.9577,"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":610927,"name":"Yoon‐Mi Chung","orcid":"0000-0001-9721-9444","position":1,"is_corresponding":false},{"id":1044879,"name":"Monaben Patel","orcid":null,"position":2,"is_corresponding":false},{"id":228049,"name":"Nima Sharifi","orcid":"0000-0003-1281-3474","position":3,"is_corresponding":false},{"id":722220,"name":"Xiuxiu Li","orcid":"0009-0003-7525-1672","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:50:25.860105Z","pmid":"40544998","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":[]}