title: Steroidogenic factor 1 promotes aggressive growth of castration-resistant prostate cancer cells by stimulating steroid synthesis and cell proliferation.
abstract: The dependence of prostate cancer on androgens provides a targeted means of treating advanced disease. Unfortunately, androgen deprivation therapies eventually become ineffective, leading to deadly castration-resistant prostate cancer (CRPC). One of many factors implicated in the transition to CRPC is the onset of de novo steroidogenesis. Although reactivation of steroid receptors likely plays a pivotal role in aggressive CRPC, little is understood regarding the mechanisms whereby prostate cancer cells initiate and maintain steroidogenesis. We hypothesize that steroidogenic factor 1 (SF1, NR5A1, AD4BP), a key regulator of steroidogenesis in normal endocrine tissues, is expressed in CRPC where it stimulates aberrant steroidogenesis and fuels aggressive growth. Notably, SF1 is not expressed in normal prostate tissue. Our results indicated that SF1 was absent in benign cells but present in aggressive prostate cancer cell lines. Introduction of ectopic SF1 expression in benign human prostate epithelial cells (BPH-1) stimulated increased steroidogenic enzyme expression, steroid synthesis, and cell proliferation. In contrast, data from an aggressive human prostate cancer cell line (BCaPT10) demonstrated that SF1 was required for steroid-mediated cell growth because BCaPT10 cell growth was diminished by abiraterone treatment and short hairpin RNA-mediated knockdown of SF1 (shSF1). SF1-depleted cells also exhibited defective centrosome homeostasis. Finally, whereas xenograft experiments in castrated hosts with BCaPT10 control transplants grew large, invasive tumors, BCaPT10-shSF1 knockdown transplants failed to grow. Therefore, we conclude that SF1 stimulates steroid accumulation and controls centrosome homeostasis to mediate aggressive prostate cancer cell growth within a castrate environment. These findings present a new molecular mechanism and therapeutic target for deadly CRPC.
authors.affiliation: Department of Comparative Biosciences (S.R.L., J.S.J.), University of Wisconsin, Madison, Wisconsin 53706; University of Wisconsin Carbone Cancer Center (J.S.J., W.A.R.), Madison, Wisconsin 53792, Environmental Health Division (C.J.H.), Wisconsin State Laboratory of Hygiene, Madison, Wisconsin 53706; Wisconsin National Primate Research Center (C.J.H., T.Z.) Madison, Wisconsin 53715; Institute of Clinical and Translational Research (J.S.J., C.J.H., T.Z., W.A.R.), University of Wisconsin, Madison, Wisconsin 53705; and Department of Urology (W.A.R.), University of Wisconsin, Madison, Wisconsin 53792.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Lewis
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Hedman
authors.forename: Toni
authors.initials: T
authors.lastname: Ziegler
authors.forename: William A
authors.initials: WA
authors.lastname: Ricke
authors.forename: Joan S
authors.initials: JS
authors.lastname: Jorgensen
mesh_terms: D000728:Androgens / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D054339:Steroidogenic Factor 1