Abstract 2115: Interrogation of mechanisms that underlie augmented steroidogenesis in castration-resistant prostate cancer

Abstract

Abstract The conversion of adrenal androgens, such as dehydroepiandrosterone (DHEA), to dihydrotestosterone (DHT) drives castration resistant prostate cancer (CRPC) progression. No mutations or variations in those steroidogenic enzymes have been identified as responsible for the phenotype of increased intratumoral DHT synthesis in CRPC. By analyzing CRPC cell line models and clinical samples from patients with CRPC, we found that a gain-of-stability mutation in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1, encoded by HSD3B1 gene) confers an increase in metabolic flux from DHEA to DHT in CRPC. The prolonged protein half-life of mutant 3βHSD1 results from resisting an association with the ubiquitin E3-ligase autocrine mobility factor receptor (AMFR). Genetic selection for mutant 3βHSD1 is evident from somatic mutation in human CRPC tumors, by loss of heterozygosity (LOH) of the wild type copy in patients with heterozygous inheritance, and from acquisition of same somatic mutation in a mouse xenograft tumor model treated with abiraterone. Furthermore, we found the expression of AMFR is suppressed in a CRPC xenograft model expressing wild type 3βHSD1, suggesting a compensatory mechanism that augments steroidogenesis in CRPC progression. Our discovery of this 3βHSD1 gain-of-function mutation is the first example of a mutation identified in a component of steroidogenic machinery in CRPC, which strongly validates a new target for individualized cancer therapy in CPRC. Citation Format: Kai-Hsiung Chang, Nima Sharifi. Interrogation of mechanisms that underlie augmented steroidogenesis in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2115. doi:10.1158/1538-7445.AM2014-2115