PROJECT SUMMARY Tamoxifen is an estrogen-like drug that is used to treat breast cancer patients, breast cancer survivors, and patients with a family history of breast cancer. As a treatment, tamoxifen is extremely effective at decreasing the changes of getting cancer and increasing patient survival. The goal of our research is to understand how tamoxifen may affect other estrogen-sensitive tissues, specifically the hypothalamus. We hypothesize that tamoxifen alters estrogen receptor signaling in the hypothalamus and that this dysregulation underlies the generation of hot flashes in patients undergoing tamoxifen therapy. We will use cutting-edge molecular tools to define the tamoxifen-sensitive cell types within the hypothalamus and genetically engineered mice to identify the cell types and receptors that mediate the effects of tamoxifen on temperature control. This information will help us better understand how tamoxifen therapy impacts the brain. Ultimately, this information could be used to design treatments or adjuvants that provide relief from the side effects of tamoxifen and improve quality of life for breast cancer patients and survivors.