The androgen receptor (AR) makes profound contributions to the biology of prostate cancer cells, principally through its function as a ligand-regulated transcription factor. As such, therapeutic approaches to prostate cancer are typically designed to deplete or compete with endogenous androgens with the goal of reducing the transcription function of AR. This proposal addresses a relatively unexplored area of AR action, which is how it generates and responds to DNA damage. In brief, we have developed a large set of preliminary data that shows AR is part of an signaling axis that is initiated by androgen, requires inputs from the DNA damage and repair machinery, and results in assembly of a DNA repair complex. We found that one of the key enzymes in this pathway is Parp7, a mono-ADP-ribosytransferase for which little is known.
In Aim1 we will determine how Parp7 is regulated by androgen and DNA damage signaling in prostate cancer cells.
In Aim2 we will determine how Parp7 regulates the assembly and DNA repair function of an E3 ubiquitin ligase/ADP-ribosyltransferase complex.
In Aim3 we will define the contribution of the signaling axis to genome maintenance, tumorigenesis, and therapy response. The enzymes that mediate DNA damage response and repair reactions have emerged as actionable targets in malignancies including prostate cancer. Inhibitors to the poly-ADP-ribosyltransferase family member, Parp1, improve outcomes in therapy- resistant prostate cancer, though the benefit depends on the status of the DNA repair machinery, notably the BRCA1/BRCA2 genotype. Thus, while the clinical findings provide proof-of-principle for targeting DNA repair pathways, they also underscore the importance of defining and incorporating biochemical and genomic context into treatment rationale. In summary, our studies will define the biochemical relationships between androgen signaling and DNA damage and repair pathways, and help provide new insights into the vulnerabilities of prostate cancer cells.
Prostate cancer remains the second leading cause of deaths due to cancer in North American men. Defining the communication pathways within prostate cancer cells, which is to say, how proteins talk to each other, is critical for discovering and improving drugs that kill prostate cancer cells. We have identified a new communication pathway that operates in prostate cancer cells, and we propose to determine how it works, and whether manipulating the pathway will inhibit prostate cancer cells.
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