MAMMARY REGULATION BY TRANSFORMING GROWTH FACTOR BETA

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We have recently obtained the first evidence for a possible inhibitory role in vivo for Transforming Growth Factor-Beta (TGF-Beta), a peptide previously identified with a variety of effects on cultured cells, including inhibition of proliferation of various epithelia in culture. Using small plastic "Elvax" implants capable of sustained, local release of TGF-Beta when implanted directly into tissues, we found that TGF-Beta dramatically inhibited the growth of mammary ducts in vivo. The effect was fully reversible and appeared in all respects to mimic the natural process of growth regulation in the gland. Inhibition of cell proliferation by tissue factors in thought to be a major, though poorly understood homeostatic influence operating in normal tissue growth and maintenance. This negative growth regulation is of special significance to the cancer problem; a critical feature of malignant cells is their ability to proliferate in the presence of regulative influences that restrain the growth of normal cells. Using the mammary-Elvax system to provide a quantitative measure of growth regulation, we propose to expand our preliminary findings as follows: 1. Characterize growth regulation by TGF-Beta, obtaining data on the time course, dose-dependency, reversibility, and other features of inhibition. Precancerous and cancerous mammary tissues will be studied as well as several normal growth stages. 2. Mechanisms of growth inhibition will be investigated by examining interactions of TGF-Beta with other growth factors and hormones, and by determining receptor localization and ligand binding characteristics. 3. The hypothesis that TGF-Beta is a naturally occurring growth regulator in the mammary gland will be tested. Its production in vivo and in cultured mammary cells will be directly assayed, and TGF-Beta gene activity will be determined. Using specific antibody released locally from Elvax implants, the effects of neutralization will be determined. Influences of TGF-Beta on cell differentiation and on epithelial-stroma relations will be investigated.