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 D

SUBMITTER: Li X 

PROVIDER: S-EPMC12281528 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature