Gene Regulation by Retinoid Receptors in Human Mammary Epithelial Cells

Retinoids are important mediators of normal growth and differentiation of epithelial cells and may play an important role in the chemoprevention of breast cancer. While normal mammary epithelial cells express retinoic acid receptors (RAR) a majority of breast cancers have selectively lost the expression of specific RAR isoforms. In order to investigate the molecular mechanisms by which loss of retinoic acid receptor function might promote the malignant transformation of mammary epithelial cells, we have inhibited retinoic acid receptor function in normal human mammary epithelial cells (HMECs). We observe that suppression of retinoic acid receptor function in HMECs results in dysregulated growth and inhibits structural differentiation. These observations lead us to hypothesize that retinoids and retinoic acid receptors may be important in regulating mammary epithelial cell growth and differentiation. and therefore, loss of retinoic acid receptor function might promote breast cancer carcinogenesis. The aim of this proposal is to identify and characterize genes activated or suppressed by loss of retinoic acid receptor function in human mammary cells. It is our hope that these studies will facilitate the understanding of normal mechanisms controlling growth and differentiation of HMEOs and provide insight into how these normal processes may be altered in breast cancer.