The transformation of the prostate epithelium, and progression to invasive carcinoma, involves de-regulation of the differentiation process, increased proliferation and decrease in apoptosis. A family of transcriptional regulators, known to regulate all these processes, is the Inhibitor of differentiation (Id) protein (Id1, Id2, Id3 and Id4) family. The Id proteins primarily function as dominant negative regulators of basic helix loop helix (bHLH) protein activity but can also modulate the activity of non-bHLH proteins such as Ets, PAX and Rb. Consequently, Id gene expression is elevated in undifferentiated tumor cells, supporting their role as inhibitors of differentiation and growth promoting factors. Increased Id1 expression is also associated with increasing grade of PCa. Our recent studies demonstrate that Id1 and Id3 initiates immortalization of primary prostate epithelial cells, promotes aggressiveness and its loss blocks proliferation of PCa cells. Given this critical role, the Id genes are considered as diagnostic markers and therapeutic targets in PCa. In spite of this significance, the underlying molecular mechanism of action of Id genes is far from clear. For example, do Id1 and Id3 have over-lapping functions or target unique pro-tumor and/or anti-tumor pathways? This proposal was therefore designed to test our first hypothesis thatId1 and Id3 promote PCa by acting as regulators of unique pro-tumor and anti-tumor pathways. Our recent studies have also shown that Id4 acts as a tumor suppressor, a function that is distinct as compared to tumor promoters Id1-3. What is the molecular basis of this unique function of Id4? In order to address this question, we propose our second hypothesis that Id4 may act as a tumor suppressor by modulating the signaling pathways or by altering the transcriptional program. The non over-lapping isoform specific functions clearly suggest that the downstream events elicited by Id genes are unique that needs to be determined. Understanding these molecular mechanisms of action of Id proteins will have significant implications on defining the role of these proteins in PCa and their overall biology. The following specific aims are proposed: 1) Examine the expression of Id1-4 in prostate, 2) Investigate the significance of increased Id1/3 expression in PCa and 3) Determine the molecular mechanism of action of Id4. Completion of these studies will allow us to better understand: a) the molecular mechanisms involved in the initiation/ maintenance of PCa b) biology of Id proteins and c) the significance of Id isoforms as diagnostic markers and therapeutic targets. The emerging hypothesis addressed is that Id isoforms have unique functions that integrate their pro- and anti-tumor pathways at multiple levels in PCa. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to understand the role of Id (inhibitor of differentiation) family of transcriptional regulators in prostate cancer initiation and progression. The results from this proposal demonstrating the expression and mechanism of action of Id genes in prostate cancer will help decide therapeutic intervention strategies and use of Id genes themselves as therapeutic targets.

R01CA128914

2009-09-01

2015-08-31