Androgen deprivation therapy is the standard treatment for patients with prostate cancer. Unfortunately this treatment is only palliative and eventually patients will relapse with castratio resistant tumors, which cause death. Accumulating evidence suggests that abnormal activation of androgen receptor (AR) and development of apoptotic resistant cells contribute to castration-resistant prostate cancer (CRPC) growth. AR activation in CRPC may occur by a variety of mechanisms that alter the sensitivity or specificity of AR. Our published and preliminary data demonstrate that NF-?B2/p52 (p52) is overexpressed in prostate cancer and overexpression of p52 facilitates CRPC progression through activating AR signaling and protecting cells from apoptotic death induced by androgen deprivation therapy. p52 interacts with and activates the AR under androgen deprived conditions and increases expression of many androgen regulated genes including prostate-specific antigen (PSA). p52-activated AR binds to the distal region, but not the proximal regions of the PSA promoter, whereas, DHT-activated AR binds to both the proximal and distal enhancers of the PSA promoter, suggesting that p52-activated AR is conformationally different from DHT-activated AR. We further demonstrate that p52 decreases the expression of microRNA let-7 and increases the expression of Lin28, a master negative regulator of let-7. Based on these findings, we hypothesize that NF-?B2/p52 plays a critical role in the development and progression of prostate cancer. There are three specific aims of this proposal. 1. Determine the functional roles of p52 in prostate cancer.
This aim focuses on defining the role of p52 in AR activation and prostate cancer progression using androgen-sensitive prostate cancer cell models that expresses a wild-type AR and p52 in a physiological range. p52 will be inducibly expressed in the androgen-responsive, p52-negative LNCaP and LAPC-4 (expressing wild type AR) human prostate cancer cells to further test the effect of p52 on androgen-mediated prostate cancer cell growth in vitro and in vivo. In addition, we will determine the causal role of p52 in prostate cancer development and progression in the established transgenic mouse model. 2. Characterize the p52-activated AR transcriptional com-plexes. ChIP-Seq analysis will be used to perform comprehensive, high-resolution mapping of p52-activated AR genomic recruitment sites and to compare the resulting profile with that of the classical, steroid-activated receptor. 3. Characterize the p52-mediated signaling pathway in prostate cancer. We will determine whether p52 regulates let-7c expression by direct transcriptional repression of its promoter or indirectly via its effect on Lin28, the master regulaor of let-7c processing. We will then determine whether let-7c mediates p52-induction of AR activation through c-myc. We will examine the effects of Lin28/let-7c on p52- mediated prostate cancer cell growth and progression in vitro and in vivo. Completion of these studies will provide the vital role of p52 signaling network in prostate cancer, and will likely present excellent diagnostic and/or prognostic indicators and potential therapeutic targets for prostate cancer.
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in the United States men. Although prostate cancer initially response to androgen deprivation therapy, virtually all patients will relapse to castration resistant prostate cancer (CRPC). Unfortunately, there is currently no effective treatment for men with CRPC. The present proposal directly deals with the mechanisms of this evolution of CRPC and has identified a novel factor involved in this process. Our hypothesis is that p52 activation promotes the development and progression of prostate cancer. In this proposal, we will study the role of p52 during prostate cancer progression to castration-resistance. Thus, this project targets CRPC, a very significant health problem among male veterans. Completion of this study will significantly enhance current understanding of the mechanism of CRPC.