Micronutrients are known to play a central role in regulating a variety of biological processes, like cell proliferation. Vitamin A and its derivatives (retinoids) regulate gene expression by acting as ligands that modulate transcription by binding to specific nuclear receptors. These ligand-receptors complexes then bind to cognitive response elements and modulate gene transcription. Our group has a long-standing interest in nuclear receptors for retinoic acid, and how these receptors function to inhibit cell growth. In this proposal, we hope to extend these studies to identify how the micronutrient, all-trans retinoic acid functions to inhibit cell growth in the mammary gland, first in vitro and then, in vivo. Initial studies will test the hypothesis that the ligand, retinoic acid, plays a central role in the ability of one nuclear receptor, RARbeta2, to inhibit cell growth, using ligand binding mutants of this receptor. We will then extend these studies to identify what specific cells in the mammary gland in vivo express RARbeta2, and how hormones effect the expression of this gene. Finally, using differential display, we hope to identify genes, both known and novel, regulated by retinoic acid, which may function to inhibit cell proliferation in the mammary gland. In this way, we hope to generate a framework to better understand how this micronutrient regulates the structure and the function of the normal mammary gland.
