Elevated androgen receptor (AR) activity and PI3K-Akt signaling are involved in prostate cancer development and progression. The mechanisms responsible for elevation of these two key signaling pathways in prostate cancer, however, have not fully elucidated. We found that Vav3 oncogene, a quanine nucleotide exchange factor (GEF) for Rac/Rho GTPases, is overexpressed in androgen-independent prostate cancer cells and in 32% of human prostate cancer. Further analysis revealed that Vav3 stimulates growth of prostate cancer cells, interacts with AR via the DH domain, and activates AR as a coactivator. Vav3, as a signal transducer, also upregulates PI3K-Akt signaling leading to AR activation. Furthermore, targeted overexpression of Vav3 in the prostate epithelium induces prostatic intraepithelial neoplasia (mPIN) in young adult mice as early as two months old. We hypothesize that overexpression of Vav3 inappropriately activates AR and promotes prostate cancer development and that further elevated Vav3 activity stimulates prostate cancer progression to the androgen-independent status.
Three Specific Aims are proposed to test the hypothesis.
Specific Aim 1 : To determine the role of Vav3 overexpression in prostate cancer development and progression to the androgen-independent status in mouse prostate cancer models. We will investigate whether forced overexpression of Vav3 stimulates androgen-independent growth in prostate tumor and whether targeted overexpression of Vav3 in the prostate epithelium induces prostate cancer development and stimulates progression to the androgen-independent status in transgenic mice.
Specific Aim 2 : To elucidate the signaling pathways of Vav3 in prostate cancer. We will determine the underlying molecular mechanisms of Vav3 coactivation for AR and Vav3 signaling via the conventional Vav3-Rho-PI3K-Akt pathway leading AR activation in prostate cancer cells. We will also build up the whole Vav3-mediated signaling pathways that connect extracellular stimuli to AR signaling axis as well as cell growth and survival pathway by GST-pull down and Mass Spectrometry-based proteomics analysis.
Specific Aim 3 : To associate Vav3 overexpression with Gleason score, pathologic stage, PI3K-Akt signaling, and androgen-independent status in human prostate cancers. Once completed, these studies from the preclinical mouse model to the clinical study in human prostate cancer specimens will further our understanding of the mechanisms of prostate cancer development and its androgen-independent growth and provide targets and animal models for the rational development of novel therapies against prostate cancer. ? ? ? ? ? ?
