DOWN REGULATION OF METASTASIS SUPPRESSOR GENE PREDICTING PROSTATE CANCER BEHAVIOR

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Presently, one of every four cancers diagnosed in American males is of prostatic origin. Once prostatic cancer metastasizes, it is a fatal disease for which curative therapy is not available presently. Because of these facts, there is a growing interest in aggressive screening of men for prostate cancer to allow early detection of prostatic could potentially identify 10 million American men with cancer cells histologically detectable within their prostates. It is estimated that approximately 7% (700,000) of these men will eventually die from progression of these cancer cells. This raises the critical question as to which of the remaining 93% (9,300,000) of men with nonlethal, but potentially life-altering, histologically detectable prostatic cancer to be substaged into those requiring immediate therapy vs no treatment. Acquisition of metastatic ability by such histologically detectable prostatic cancer cells is a definitive criterion upon which to base such a diagnostic substaging method. Thus, detection of specific molecular changes definitely associated with acquisition of metastatic ability by prostatic cancer cells could be used in combination with histological grading to appropriately substage and thus individualized the treatment of patients with histologically detected prostatic cancer. Studies in the PI's laboratory have demonstrated that acquisition of such metastatic ability by prostatic cancer cells involves not only increased expression of certain oncogene(s) but also decreased expression of certain other metastasis suppressor gene(s). Thus, the specific aims of this project are: 1) to determine the chromosomal locations within the human genome of these metastasis suppressor gene(s) for prostatic cancer, 2) to clone the expressed gene(s) located within these specific human chromosomal regions, 3) to develop antibodies for the immunocytochemical detection of loss of expression of these metastases suppressor gene products by prostatic cancers and 4) to determine if down-regulation or lack of expression of any of these gene(s) identified in specific aim 2 can be used to predict the metastatic ability of human prostatic cancers. Using this approach, at least one such metastatic suppressor gene (termed the Kai-1) has been identified, cloned, and mapped to human chromosome 11p11.2 for prostatic cancer during the previous 2 years of SPORE support.