New Insight of Androgen Signaling in Prostate Cancer Initiation and Progression

Project Summary Prostate cancer is one of the most common malignancies in men and claims about 30,000 deaths annually in the United States. The androgen-signaling pathway mediated through the androgen receptor (AR) and its ligands, testosterone and 5α-dihydrotestosterone (DHT), is essential for prostate tumorigenesis. Multiple lines of evidence have implicated a promotional role of androgen signaling in prostate cancer growth, survival, and progression. The AR is a nuclear hormone receptor. Although the targets of AR activation in prostate tumorigenesis still remain unclear, they appear critical for promoting cell proliferation because most primary prostate cancers express the AR and are androgen-dependent. Therefore, androgen deprivation therapy (ADT) still remains the first-line treatment for advanced prostate cancer currently. While the treatment initially achieves dramatic therapeutic response, it eventually fails in nearly all patients. Consequently, the patients develop castration resistant prostate cancer (CRPC) after 2-3 years following the therapy, for which there is no curative treatment. Currently, the molecular mechanisms underlying prostate cancer progression and CRPC development remain largely unknown. Previous data from others and ourselves imply that androgen-independent prostate tumor cells may still be “AR dependent,” and thus that the AR and related signaling pathways can be targeted for treating castration sensitive and resistant prostate cancer. However, the oncogenic role of the AR in inducing prostate cancer progression and CRPC development is still largely unknown. One of the bottlenecks for limited progress in the field has been the lack of appropriate animal models that can directly recapitulate the oncogenic role of AR during prostate cancer initiation, progression, and hormone refractoriness. To address this significant need, we have developed a new AR transgenic mouse line and several related mouse models that can mimic AR action as seen in human prostate cancer cells. We will use these novel, biologically relevant models together with human prostate cancer patient derived cell lines and xenograft models and state-of-the-art experimental approaches to assess aberrant AR activation in promoting ligand-dependent and -independent tumor growth and progression. Specifically, we will address our central hypothesis that aberrant AR activation originated in prostatic AR-expressing cells dysregulates and interacts with oncogenic signaling pathways to promote prostate cancer aggressiveness, progression and hormone refractoriness. To test this hypothesis, we propose the following three specific aims: 1) Identify the oncogenic role of AR in castration resistant tumor development and growth, 2) determine the oncogenic role of AR in activating IGF1 signaling in promoting prostate cancer progression and hormone refractoriness, and 3) determine aberrant AR and β-catenin co-activation in promoting prostate cancer progression, metastasis, and CRPC development.