Despite the central role of androgen receptor (AR) in prostate cancer (CaP) progression, insights into the specific molecular mechanisms by which androgens control the cellular processes that drive CaP progression remain largely elusive. Lack of this knowledge is an important problem, because without it, development of novel therapeutic approaches that target specifically androgen-dependent events underlying the lethal phenotype is unlikely. The long-term goal is to understand how the mechanism(s) by which androgens control clinically relevant gene expression in CaP cells can be manipulated for therapeutic intervention. The objective is to determine the molecular mechanism(s) by which androgens control activity of Serum Response Factor (SRF) and the relevance of these mechanisms for CaP progression. The central hypothesis is that the SRF- responsive subset of androgen-regulated genes is responsible for the aggressive CaP phenotype via androgen activation of the RhoA signaling axis and the RhoA effectors PKN1 and CIT. This hypothesis is formulated based on preliminary work produced in the applicant's laboratory. The rationale for the proposed studies is that, once it is understood how androgen regulation of SRF action in CaP occurs, select targeting of androgen action that is relevant to disease progression will be possible. The central hypothesis is tested by pursuing 3 specific aims: 1) define the contribution of RhoA, PKN1 and CIT in androgen regulation of SRF target genes;2) determine the preclinical role of the SRF-responsive subset of androgen-regulated genes in CaP cell motility and invasive behavior;and 3) determine the clinical relevance of RhoA-, PKN1-, and CIT-dependent androgen- responsive SRF action.
Aim 1 uses a custom gene expression assay to determine the contribution of RhoA, PKN1 and CIT to androgen regulation of SRF target genes, and the manner in which PKN1 and CIT convey androgen control to SRF is established.
Aim 2 uses preclinical models to identify SRF target genes, PKN1 and CIT as targets to impair CaP cell invasiveness.
Aim 3 uses a combination of in silico analysis and tissue microarray analyses to determine the relevance of PKN1, CIT and SRF effector genes for CaP progression. The proposed research is innovative because it focuses on an entirely different approach to target androgen action in CaP: unraveling and targeting an androgen-dependent signaling pathway downstream of AR that controls the expression of genes that are relevant for CaP progression. This contribution is significant because is it the first step in a continuum of research that is expected to lead to the development of novel treatment modalities that target specifically androgen-mediated gene expression that underlies the lethal CaP phenotype. With respect to expected outcomes, the proposed studies will identify the molecular mechanisms by which the SRF-dependent mechanism of androgen action gives rise to the aggressive CaP phenotype. These results will have an important positive impact because they will fundamentally advance knowledge about androgen action in CaP, in general, and provide new targets for CaP-specific therapy, specifically.
The proposed research is relevant to public health because insights into the specific molecular mechanisms by which androgens control prostate cancer (CaP) progression are ultimately expected to provide the foundation to develop novel treatment options that are tailored to the specific androgen-dependent events that underlie the lethal phenotype of CaP, a malignancy that affects 1 in 6 men in the US. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help reduce the burdens of human cancer.
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