This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The heterogeneity of prostate cancer suggests that the pathways that lead to malignant transformation are not uniform but certain genetic alterations and pathways may be common in the initiation leading to malignancy. The progression to invasive carcinoma is characterized by de-regulation of differentiation process, leading to an increase in the proliferation and a corresponding decrease in apoptosis. The transcription factor family, which is known to regulate both these processes, is the basic helix-loop-helix bHLH family. The Id (Inhibitor of differentiation) proteins function as natural negative regulators of bHLH protein activity through the formation of inactive heterodimers with bHLH transcription factors. Consequently, Id gene expression is elevated in undifferentiated, proliferating and tumor cells. The Id proteins also function at multiple levels and its interactions may not be limited to bHLH proteins. Over-expression of Id proteins results in apoptosis and/or cell proliferation. The ability of Id to stimulate the cell cycle, activate telomerase and immortalize cell types suggests that Id proteins may act as oncogenes or cooperating oncogenes. Our recent results suggest that the functions of Id proteins in prostate cancer cell lines are non-redundant. Id1, Id2 and Id3 are potential oncogenes or cooperating oncogenes and surprisingly, Id4 acts as a tumor suppressor. Id1 and Id3 target cell proliferation pathways, Id2 targets apoptosis and Id4 acts as a tumor suppressor by inducing the expression of p53, E-cadherin and androgen receptor (AR) in AR-ve prostate cancer cell line. Interestingly, Id3 copy number is also increased in DU145 prostate cancer cell line. Hence Id proteins represent a new paradigm in prostate cancer biology that needs to be carefully examined. Increased expression of Id1, Id2 and Id3 proteins has been reported in primary human tumors including human prostate and cultured tumor cells, whereas Id4 expression is lost in many cancer cell lines and tissues possibly due to promoter hypermethylation. Preliminary studies have demonstrated that loss of function of Id1/ Id3 and Id2 blocks proliferation and apoptosis respectively, whereas gain of Id4 functions initiates an epithelial phenotype and re-emergence of AR receptor expression in model prostate cancer cell lines. The present study is therefore designed to test the hypothesis that """"""""Id genes (Id1, Id2, Id3 and Id4) have non-redundant functions and their expression levels, copy number changes (Id3) and promoter methylation status (id4) are sensitive prognostic markers strong therapeutic targets for the management of the disease"""""""". The novel ideas that are being pursued in this proposal are the copy number changes in Id3 and the role of Id4 as a tumor suppressor in prostate cancer.
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