Breast cancer accounts for 27% of all cancer in women, and at present, metastatic breast cancer cannot be cured. The prevalence of this disease and its refractory nature provide a strong rationale for the development of new therapeutic approaches for metastatic breast cancer. The goal of this proposal is to explore new treatments for and to obtain a better understanding of the biology of breast cancer. Preclinical data indicates that retinoic acid derivatives inhibit the proliferation of estrogen receptor-positive (ER+) breast cancer cells, and are synergistic in this effect with antiestrogens. Therefore, we plan to study the effects of a combination of retinoid and antiestrogen therapy in patients with estrogen and/or progesterone receptor-positive (ER+ and/or PR+) metastatic breast cancer, and to analyze tumor tissue from these patients for molecular markers that could define subsets of patients more likely to respond to such therapy. Since retinoid effects are mediated by various subtypes of nuclear retinoid receptors, 9-cis retinoic acid (9-cRA) is an excellent retinoid to employ in this study of the correlation between clinical retinoid response and receptor expression because it binds to the broadest range of retinoid receptor subtypes of any retinoid with known receptor specificity. The specific aims of this proposal are: to conduct a phase I clinical trial of 9-cRA and tamoxifen (tam) in patients with metastatic breast cancer in order to determine the maximal tolerated dose and the toxicities of this combination; to conduct a phase II clinical trial of 9- cRA and tam as first line hormonal therapy for metastatic disease in patients with metastatic breast cancer with positive BR and/or PR, and to assess the response rate, duration of response, and survival in these patients; to determine the levels of both mRNA and protein (by in situ hybridization and immunoprecipitation/Western blotting, respectively) for the various types of retinoid receptors, including the retinoic acid receptors (RARs alpha, beta, and gamma), the retinoid X receptors (RXRs alpha, beta, and gamma), and the retinoid orphan receptors (ROR/RZRs), in breast cancer tissue obtained both at original presentation and at the time of metastatic tumor biopsy; to make observations about the relationship between levels of specific RAR, RXR, or ROR/RZR subtype mRNA or protein and clinical response to 9-cRA in combination with tam; and to assess the levels of the various RAR, RXR, and ROR/RZR mRNAs and proteins both in tumor samples and in a variety of breast cancer cells lines in order to determine whether a predictable relationship exists between levels of mRNA and protein for each specific retinoid receptor subtype within breast cancer cells. In this manner, we intend to both identity any possible correlation between response and retinoid receptor status, and to gain a better understanding of the mechanism by which retinoids and tam are synergistic in the inhibition of breast cancer growth.