Breast cancer will be newly diagnosed in 120,000 women in the United States yearly over the next 5 years and 1/16 women will develop this disease in her lifetime. Prostate (86,000 new cases/year) and endometrial) carcinoma (38,000 new cases/year) are also common hormone-dependent cancers. This Program Project investigates basic mechanisms of the hormonal control of mitosis in breast, prostate and endometrial cells and applies these findings to the development of treatment strategies in patients. The general approach is to determine how hormones increase the proliferative rates of hormone-dependent cells in an autocrine fashion and influence the growth of surrounding hormone-independent cells via paracrine mechanisms. Project 1 consists of a randomized, controlled clinical trial of hormone priming plus chemotherapy in prostate cancer patients. Flow cytometry and CAS- 1OO image analysis are used to systematically evaluate the cell cycle effects of hormones on tumor cells. Projects 2A and 28 evaluate the basic physiologic role of hormones, polyamines and growth factors in the proliferation of breast cancer cells in vivo and in vitro. Project 3 employs a nude mouse xenograft system and cell culture to grow hormone-dependent human endometrial tumors. The effects of various combinations of simultaneous, separate and intermittent hormonal therapies are assessed with regard to tumor growth and cell cycle kinetics. Project 4 systematically investigates the effects of androgens on cell cycle duration and growth fraction and rate of cell loss in various prostate models. This information is applied to evaluate the effects of chemotherapy during androgen-stimulated mitosis. In Project 5, the roles of uptake, local production, binding and metabolism on tissue estradiol levels are investigated in NMU and human mammary tumors. Inhibitors of in situ estradiol synthesis are used to modify breast tumor mitotic rates. Project 6 evaluates the biologic significance of clusters of endometrial carcinoma cellular markers including DNA index, presence of ER, PgR, transferrin receptor and Ki67 antigen. Project 7 utilizes the monoclonal antibody raised against the Progesterone receptor to evaluate biologic effects of hormones on PgR structure (isoform, subunits), on structure function relationships, and on regulation of tissue receptor functionality. Core facilities include the Cell Identification/Cell Kinetic Laboratory, the Core Endocrine Laboratory, the Biostatistical Unit, and the Educational Unit.
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