The Molecular Mechanisms of Androgens/Androgen Receptor Deficiency on the Formation of Neuroendocrine Phenotype and Neuroendocrine Prostate Tumors (Ii)

The androgen deprivation therapy (ADT) has been a standard treatment for prostate cancer and effective for inhibition of luminal epithelial tumors, but eventually patients show signs of androgen-independent progression and progress into hormone-refractory stage, for which no optimal therapeutic options are currently available. Recently, several groups demonstrated that the prostate adenocarcinomas (PCa) with neuroendocrine (NE) prostate tumors are associated with androgen independence and NE status was significantly increased in patients with hormone-refractory PCa following long-term androgen deprivation therapy. In our preliminary studies, we have discovered that the neurite outgrowth of these NE cells was significantly inhibited upon androgen treatment, suggesting a suppressive role of androgen receptor (AR) in these NE cells. In contrast, it was well known that androgen/AR stimulates the growth of prostate luminal epithelial cells suggesting the AR have promoting roles in luminal epithelial cells. Therefore, we hypothesize that androgen/AR is required for the growth of epithelial cell and inhibition of NE differentiation in prostate cancer. Loss of AR or androgen deprivation therapy may significantly increase NE prostate carcinoma formation. We have silenced the AR in PCa by crossbreeding androgen receptor knockout (ARKO) mice with murine transgenic TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) model of prostate NE tumors. We will monitor AR levels and actions in the PCa with NE prostate tumors and plan to accomplish this project by pursuing the following specific aims: Aim 1: To determine whether loss of AR activates FoxA2/Smads pathway to induce NE-like cell growth, differentiation and decreased cell death in androgen-AR deficiency of prostate tumor. Aim 2: To study the mechanisms of loss of AR activates FoxA2/Smads signaling-mediated transcriptional programs that are required for androgen-independent growth of neuroendocrine prostate tumor. Aim 3: To investigate the opposite roles of AR in suppression of neuroendocrine cell differentiation and stimulation of epithelial cell growth in prostate cancer. This proposal work is innovative, because (1) it concerns the mechanisms of Smads/FoxA2 pathway is required for the conditional and spatial regulation of a subset of genes critical for NE phenotype and metastasis of PCa. (2) NE prostate tumor formation due to the loss of AR or androgen depletion, which then induce Smads cooperation with the NE-specific transcription factor FoxA2 as well as for development of NE prostate tumors. (3) Importantly, our study will reveal that AR is a critical suppressor for NE prostate tumors. With the success of this work, we may further develop a molecular understanding of NE prostate carcinoma and identify the downstream signaling molecules of loss of AR pathway essential for NE prostate cell growth. Together, this study will provide a useful model in identifying possible targets for therapy and markers for improved detection and monitoring of prostate cancer with neuroendocrine (NE) phenotype and NE prostate tumors.

Project ID:PC10108-0811
External Project ID:NSC101-2314-B182-037