Access Type

Open Access Dissertation

Date of Award

January 2014

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Sreenivasa R. Chinni

Abstract

Intratumoral androgen synthesis in prostate cancer (PCa) contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus, contributing to CRPC in a castrated environment. Although intratumoral androgen synthesis is thought to contribute to the development and progression of CRPC, currently little is known regarding the regulation of androgen biosynthetic enzyme gene expression in PCa. The TMPRSS2-ERG transcription factor has been shown to be present in primary PCa tumors as well as CRPC tumors. The hypothesis was investigated that TMPRSS2-ERG fusions regulate androgen biosynthetic enzyme (ABE) gene expression and the production of androgens, which contributes to the development of CRPC. Data revealed that ERG regulated the expression of ABE, AKR1C3, in PCa cells via direct binding to the AKR1C3 gene region. Knockdown of ERG resulted in reduced AKR1C3 expression, which caused a reduction in both DHT synthesis and PSA expression in VCaP PCa cells treated with 5a-Androstanedione, a DHT precursor metabolite. Immunohistochemical staining revealed that ERG was co-expressed with AKR1C3 in PCa tissue samples. These data suggest that AKR1C3 catalyzes the biochemical reduction of 5a-Androstanedione to DHT in PCa cells, and that ERG regulates this step through upregulation of AKR1C3 expression. Elucidation of ERG regulation of ABEs in CRPC may help to stratify TMPRSS2-ERG fusion-positive PCa patients in the clinic for anti-hormone driven therapies; and AKR1C3 may serve as a valuable therapeutic target in the treatment of CRPC.

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