The role of STAT -3 in androgen-dependent prostate cancer

Prostate cancer is the third-leading cause of male cancer-related deaths and the prostate gland is the leading site of new male cancer cases in Canada. Prostate tumour growth and survival is initially androgen-dependent and primary treatments include radiation and surgery. Androgen withdrawal therapy is used as a secondary treatment, to decrease the circulating supply of androgens in the body. While primary and secondary treatment can reduce tumour growth, in many cases the epithelial cells can begin to proliferate again and the tumour will acquire an androgen-independent phenotype. The objective of this thesis is to clarify the biochemical interactions that occur in IL-6 and AR pathway cross-talk. Since EGF also activates STAT-3, we included analysis of EGF cross-talk with the IL-6 and AR pathways. We investigated the potential for pathway interaction in LNCaP cells by using AR and STAT luciferase reporter constructs in the presence of IL-6, R-1881 and EGF stimulation. To verify the necessity of STAT-3 to the observed pathway interactions, we used shRNA to downregulate STAT-3 expression. In addition, we studied the role of STAT-3 in LNCaP xenograft tumour growth and serum PSA production in male nude mice. Our findings confirm that androgen can augment STAT-mediated gene transcription and growth factors such as IL-6 and EGF can augment AR-mediated gene transcription. Based on the ability of STAT-3 antisense ODN treatment to suppress serum PSA levels and tumour growth in vivo, and our in vitro findings that indicate an inability of STAT-3 shRNA to suppress EGF and IL-6-mediated augmentation of androgen-stimulated AR-mediated gene transcription, we propose that STAT-3 activation may not be directly involved in AR transactivation. Other growth factor pathways that occur in parallel to STAT-3 activation are likely responsible for AR transactivation via AR co-regulators. We conclude that STAT-3 has a role in regulating prostate cancer growth and survival, under androgen-deprived conditions, that indirectly affects AR activity.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat