NKX3.1 is a gene with prostate-specific expression that is homologous to the Drosophila NK homeobox gene family. NKX3.1 is highly expressed in adult prostate and at a much lower level in testis, but little or not at all in several other tissues. Levels of NKX3.1 mRNA are increased after androgen stimulation of the prostate carcinoma line LNCaP. The NKX3.1 gene map to chromosome locus 8p21 within approximately 2 megabases of NEFL, one of the most frequently deleted markers in prostate cancer. There is some variability in the frequency of 8p LOH in different series, but it may be as high as 70%. This implies that a tumor suppressor gene resides on 8p and is partially inactivated by loss of one of the two 8p alleles. The coding region of NKX3.1 is not mutated in prostate cancer tissues, but the promoter region has not bee studied. We have described a polymorphism, R52C that results in a nonconservative arginine->cysteine substitution at amino acid 52 in the NKX3.1 protein. The amino acid substitution causes altered binding to a DNA homeobox in vitro. Therefore, the polymorphism may be responsible for physiological differences in protein activity. The structure and expression of NKX3.1 will b investigated in prostate cancer. The R52C polymorphism will be evaluated for its impact on prostate cancer risk. NKX3.1 will be studied as a marker for prostate micrometastases. This is an exploratory proposal that seeks to determine the clinical relevance of NKX3.1. The applicant will pursue five specific aims: 1) characterize the 5 upstream region of NKX3.1 DNA for mutations in prostate cancer tissues; 2) determine the incidence of the R52C polymorphism in Caucasians, African Americans and Chinese; 3) using DNAs from two case control studies of prostate cancer, determine whether the R52C polymorphism influences prostate cancer risk; 4) determine if he can detect prostate cancer micrometastases in the peripheral blood by RT-PCR for NKX3.1 mRNA; 5) characterize expression of NKX3.1 protein in prostate cancer tissues by immunohistochemistry.
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