Since Huggins and Hodges demonstrated the androgen responsiveness of human cancer in 1941, 1 androgen ablation has remained the standard therapy for patients with advanced prostate cancer. Once tumor growth is androgen- independent, the median survival of patients is less than one year and no agent has yet been shown to improve the survival of such patients. The transitions from androgen dependence to androgen independence represents a critical juncture in the progression of prostate cancer. The Program Project;s unifying hypothesis is that aberrant androgen receptor activation causing androgen receptor-regulated gene expression in association with dysregulation of anti-apoptotic genes promotes the transition from androgen dependent to androgen-independent prostate cancer. Three hypotheses will be tested: . The transition to androgen independence is mediated by an alteration of androgen receptor function. Androgen receptor function may be altered a point mutation, CAG repeat deletion, splice variant, change in protein stability or phosphorylation and/or gene amplification. Mutations in the androgen receptor gene change the steroid binding specificity of the receptor and enhance its response to adrenal androgens. Both wild-type and functionally active mutant androgen receptors contribute to the growth of androgen-independent prostate cancer through ligand-independent mechanisms of activation. Androgen receptor regulated gene products promote the emergence of androgen-independent growth of prostate cancer cells that survive the withdrawal of testicular androgens. . Altered expression or function of protooncogenes and survival genes promotes the emergence of androgen-independence by enabling androgen responsive cancer cells to survive androgen deprivation. . Micro-environmentally-mediated epigenetic changes in gene expression support the transition from androgen dependence to androgen independence through heightened sensitive to growth stimulation by microenvironmental factors or androgen receptor mediated mechanisms. Project 1 identifies and characterizes mutations in the androgen receptor. Project 2 determines the role of androgen receptor activation and androgen regulated genes in androgen-independent prostate cancer. Project 3 examines protooncogenes/survival genes that enhance survival and growth potential of androgen-independent cells. Project 4 examines the microenvironmental effects on expression of genes involves in growth regulation. An Immunoanalysis Core will support each Project.
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