Prevention of breast cancer using medical therapy (chemoprevention) is now possible. Clinical trials havedemonstrated that treatment of normal women at high risk of breast cancer with anti-estrogen drugs(selective estrogen receptor modulators, or SERMs) can substantially reduce their risk of developing breastcancer. However, SERMs are frequently not used by high risk women because they are not 100% effectiveand because chronic therapy with anti-estrogens has significant side effects. In addition, while long-termanti-estrogens reduce the risk of ER-positive breast cancer, they do not reduce ER-negative breast cancer.Thus, more effective and less toxic strategies to prevent all types of breast cancer are needed. We havepreviously shown that RXR-selective retinoids ('rexinoids') prevent the development of ER-negative breastcancer in preclinical models in mice, and that the combination of SERMs and rexinoids is particularlyeffective. We have also conducted clinical trials using SERMs or rexinoids (as single agents) in high riskwomen and have demonstrated that these agents are tolerable. Here we will test the hypotheses that bothER-positive and ER-negative breast cancer can be prevented by combining drugs with different mechanismsof action, that by combining these drugs we will induce apoptosis in premalignant mammary tissue, and thatshort-term use of combined preventive agents will result in effective prevention with reduced side effects. (1)We will investigate whether chronic therapy with the SERM tamoxifen and the rexinoid bexarotene will totallyprevent breast cancer in the p53-null mouse model (in which both ER-positive and ER-negative breastcancers develop) and determine whether this combination therapy induces apoptosis in precancerous breastcells. (2) We will investigate whether short-term treatment with tamoxifen and bexarotene will effectivelyprevent the development of breast cancer, and we will investigate the mechanism by which this short-termtreatment can provide long-lasting protection. (3) We will conduct a Phase II clinical trial in premenopausalwomen at increased risk of breast cancer using the combination of tamoxifen plus bexarotene to determinewhether short-term treatment in high risk women will induce apoptosis or suppress proliferation of mammaryepithelial cells. These studies will lay the foundation for testing this combination of an anti-estrogen and arexinoid in women at risk of breast cancer in future Phase III breast cancer prevention trials.
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