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Gene Regulation by Retinoid Receptors in Human Mammary Epithelial Cells

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Final rept. 25 Sep 1998-30 Sep 2002

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Retinoids are important for the normal growth and differentiation of epithelial cells. We hypothesize that loss of retinoic acid receptor function might be an important early event in breast cancer carcinogenesis. In Preliminary Data we demonstrated that retinoids are important regulators of proliferation and may promote a more differentiated phenotype in normal mammary epithelial cells. To investigate the hypothesis that loss of normal retinoic acid receptor function might promote carcinogenesis of HMECs, we developed an in vitro system in which retinoic acid receptor function is suppressed by expression of a dominant-negative retinoic acid receptor DNRAR. We observe that HMECs expressing the DNRAR exhibit dysregulated growth and do not exhibit normal structural differentiation in vitro. These studies suggest that loss of retinoic acid receptor function in HMECs might result in loss of normal cellular differentiation and thereby may promote mammary carcinogenesis. We used this model system to isolate and characterize retinoid-regulated genes that may be important in the normal growth and d differentiation 0 f human mammary epithelial c ells. A 5 described in the BODY of this report, we have been successful in identifying a retinoid-regulated gene, the CREB-binding protein, CBP. CBP is a known critical regulator of retinoid-signaling, however, the role of CBP in regulating growth and epithelial cell polarity has been previously unknown. We have been able to provide evidence that CBP functions in a positive feed-back loop with retinoids and the retinoic acid receptor-beta 2. These findings provide important insight into how retinoid and retinoic acid receptors may act to regulate normal mammary epithelial cell growth and polarity.

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  • Medicine and Medical Research

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