Mechanism of Retinoid Response in Human Breast Cancer.
Annual rept. 26 Sep 94-25 Sep 95,
LA JOLLA CANCER RESEARCH FOUNDATION CA
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Retinoids, the natural and synthetic vitamin A derivatives, are well known for their inhibitory effect on the proliferation of breast cancer cells. However, the growth inhibitory effect of retinoids appears to diminish during progression of breast tumor as the effect is mainly observed in hormone-dependent estrogen receptor ER positive breast cancer cells but not in hormone- independent ER negative breast cancer cells. The goal of this research project is to investigate the molecular mechanisms by which retinoids exert their differential growth inhibitory effects on hormone-dependent and independent breast cancer cells. Our data demonstrate that retinoids can antagonize the mitogenic effect of estrogen through their negative regulation of ER transactivation activity on estrogen response elements. In addition, a loss of retinoic acid receptor 3 may be responsible for retinoid resistance of hormone-independent breast cancer cells. Furthermore, our data demonstrate that induction of apoptosis and anti-AP-1 activity contribute to retinoid-induced growth inhibition. These results largely enhance our understanding of the mechanism of retinoid action in breast cancer cells and also point to a possibility of restoring retinoid sensitivity in hormone-independent breast cancer cells.
- Medicine and Medical Research