Analysis of the androgen regulated transcriptome in prostate cancer

• Main Author: Lehman, Melanie Lynne
• Language: English
• Published: University of British Columbia 2011
• Online Access: http://hdl.handle.net/2429/39813

Prostate cancer is one of the most common cancers diagnosed and the second leading cause of cancer related death in North American men. The prostate is dependent on male-sex hormones (androgens) for differentiation and growth. Prostate cancer derived from prostatic epithelial cells is likewise dependent on androgens for survival. Androgen deprivation therapy (ADT) through pharmacological methods is currently the most effective treatment for disease no longer localized to the prostate gland. ADT offers a temporary remission, but only delays disease progression as the cancer cells adapt to survive and proliferate in castrate levels of circulating androgens. There is mounting evidence to suggest that intratumoral androgens acting through the androgen receptor (AR) continue to play a critical role in castration resistant prostate cancer (CRPC) progression. Recent advances in RNA profiling technologies are revealing a more complex picture of the human transcriptome. Alternative splice variants of protein-coding mRNAs and nonprotein- coding regulatory RNAs (ncRNA) were identified in this research that are expressed in prostate and prostate cancer cells. A custom 180K microarray was designed to profile the expression of the identified prostate RNAs, ncRNAs, and other reference RNAs. The custom microarray was used to profile expression after treatment in vitro with androgens and anti-androgens in the LNCaP prostate cancer cell line. The expression of the identified androgen regulated RNAs were examined in vivo after castration and during progression to CRPC in LNCaP xenograft tumors. The research presented is an integrative analysis of in vitro and in vivo expression profiles with ARDNA interactions detected by AR ChIP-seq and microRNAs detected by small RNA sequencing. The integrated expression profiles suggest a different androgen regulated transcriptional program in CRPC from that seen in treatment naive tumors. Several unexpected findings were revealed including a cell cycle related difference between synthetic androgen, R1881, and physiological androgen, DHT; RNAs increased by the anti-androgen, MDV3100, and not bicalutamide; and the use of alternative 3‟ UTRs following castration in the in vivo model. The identified reference and novel androgen regulated RNAs may inform on the mechanism underlying androgen deprivation therapy, anti-androgen response, and the progression to CRPC.