Prostate cancer is the second most common malignant disease among American men. There are 96,000 new cases and 26,000 deaths from prostate cancer annually. Black men in America have the highest incidence of prostate cancer of any population group in the world. The incidence among black Americans is more than twice the incidence among white Americans. Prostate cancer accounts for substantial morbidity by virtue of metastatic spread, particularly to bone, which can cause diminution in quality of life and economic productivity. More than two-thirds of prostate cancer cases present as disseminated diseases. A high proportion of disseminated prostate cancer cases are medically manageable at presentation because the cancer cells are hormone- responsive. A number of therapeutic approaches which reduce circulating androgens may cause regression or growth-arrest in these cases of prostate cancer. The cancer may be suppressed completely for up to several years, but always recurs. When it does recur it is generally hormone- unresponsive. There is no effective long-term therapy for metastatic prostate cancer which has relapsed after hormonal therapy. The purpose of the proposed work is to identify genes responsible for the progression of hormone-dependent prostate cancer to hormone-independence. A novel host/vector gene cloning system will be used to isolate cDNA clones which can confer hormone-independent growth to the hormone-dependent human prostate cancer cell line, LNCaP. The proposed work includes: 1) Construction of cDNA libraries from hormone-independent and tumorigenic cell lines. 2) Characterization of sublines of LNCaP cells for use in the host/vector system to isolate cDNA clones by phenotypic expression. 3) Isolation of cDNA clones that confer hormone-independent growth in vitro to LNCaP cells. 4) In vivo selection of cDNA clones that confer tumorigenesis to LNCaP cells. 5) Sequencing and structural characterization of cDNA clones and their expression in other cells and tissues.
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