Tamoxifen is the most commonly used selective estrogen receptor modulator (SERM) in the treatment and prevention of breast cancer. Raloxifene, a newer SERM, is currently widely used for treatment of osteoporosis and is in trials for breast cancer prevention. A new health awareness is growing among women, resulting in the use of natural supplements such as soy and black cohosh for the treatment and prevention of menopausal symptoms. Each of these substances has also been shown to contain phytoestrogens, plant derived substances, which interact functionally with ER. Therefore, there is a potential for competition between soy or black cohosh and SERMs, which may result in decreased efficacy of the prescribed medication. It is essential to know whether this interaction exists and what ramifications it may have in order to properly counsel patients about the combined use of SERMs and phytoestrogen containing natural supplements. We hypothesize that the natural products soy and black cohosh and/or their metabolites will alter the effects of tamoxifen and raloxifene on 1) ER-dependent transcription and cellular proliferation in vitro and 2) anti-tumor efficacy in a human breast cancer xenograft model in nude mice. The ultimate objective of this study is to determine the safety of combined use of SERMs and natural product dietary supplements. To begin to address this long-term goal, we plan to: 1) Determine effects of addition of genistein, daidzein, equol, and 27-deoxyactein to tamoxifen, its metabolites, and raloxifene on ER-signaling of MCF-7 human breast cancer cells and proliferation of MCF-7 and MDA-MB-231 ceils in vitro. 2) Determine effects of addition of soy and black cohosh to tamoxifen and raloxifene on ER-signaling of MCF-7 cells and proliferation of MCF-7 and MDA-MB-231 cells in vitro in a simulated system of human colonic fermentation and hepatic metabolism. 3) Determine pharmacokinetics of black cohosh in female volunteers. 4) Determine pharmacokinetics of black cohosh and soy in immunocompetent mice. 5) Determine interactions between ingested standardized soy or black cohosh and tamoxifen on MCF-7 breast cancer growth in an in vivo nude mouse model. The sponsors of the proposed study and the laboratories in which the candidate is working have extensive experience in isolation and characterization of natural products and in cancer research, which is essential to accomplishing the scientific goals outlined here as well as facilitating the development of the candidate into a productive independent investigator.
