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Prostate cancer is a leading cause of death in men. Localized and benign types of prostate cancer can be effectively eradicatd through surgery and radiation treatments. However, malignant types of prostate cancer are incurable. Therefore, identifying markers that will distinguish benign prostate cancers from the lethal types will be crucial in devising successful therapies to cure malignant prostate cancers.

Members of the Polycomb (Pc) group of proteins (PcG), necessary for transcriptional silencing, have been identified as oncogenes with cell-type specific transforming capabilities. Overexpression of some Pc genes is closely associated with several types of cancers such as breast and prostate. The Cbx7 protein controls growth of prostate cancer cells through the Ink4a/Arf locus. the same locus has also been implicated in regulation of stem cells proliferation and senesence through Bmi1, a member of the PRC1 complex. Consequently, there is a delicate balance between maintenance of multipotentiality and ability to proliferate. Therefore, characterization of the Pc complexes will be a key to understanding that balance.

The Ink4a/Arf locus, as well as the Rb and p53 pathways, has been implicated as a major cause of human cancer. the Ink4a/Arf licus encodes p16Ink4a and p14Arf, which block cell proliferation. p16Ink4a is a cyclin-dependent kinase inhibitor that favors the Rb repression pathway by inhibiting the cyclin D - CDK4/6 complexes. p14Arf induces the p53 pathway by inhibiting Mdm2 function. Fibroblasts isolated from Bmi1-null embryos undergo rapid senesence caused by the increased expression of p16Ink4a and p14Arf. However, overexpression of Bmi1 results in decreased p16Ink4a and p14Arf levels, leading to to an extension of cellular life span.

The biochemical mechanism linking the Pc proteins and the above signaling pathways is not well understood. Determination of the interplay between the Polycomb complexes and their regulation of the Ink4a/Arf signaling pathway will shed light on the mechanism of cancer progression. Therefore, my goal is to understand the process of prostate cancer progression from the androgen dependent to the androgen independent state by characterizing the Pc complexes that control chromatin function at a key cell cycle checkpoint.

Our experiments on prostate cancer xenografts show overexpression of Bmi1 protein in androgen independent samples while androgen dependent xenografts have basal levels of Bmi1. We also study the mechanism of PRC1 and Bmi1 silencing using immobilized template assays. Those studies give us an insight into the role of excess Bmi1 in preinitiation complex formation in transcription.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA