PROJECT SUMMARY Every year breast cancer causes the death of around 40,000 women in the United States, highlighting the need to improve the options to treat this disease. This proposal focuses on late stage breast cancer, where the cancer cells have spread (metastasized), and for which the median survival is approximately 3 years from the time of diagnosis. We will test whether the location of breast cancer spread – which can include the liver, the lung, and brain – alters the sensitivity of the breast cancer cells to chemotherapy. In Specific Aim 1, we will establish models of breast cancer metastases to different sites and then test the relative response to chemotherapeutic drugs. In Specific Aim 2, we will explore the extent to which host factors, including host immune system cells, can alter the pattern of dissemination of breast cancer metastases and their response to chemotherapy. Our hypothesis is that breast cancer metastasis to different organs results in organ-dependent sensitivity of the tumor cells to anti-cancer agents. Overall this project will explore the extent to which the location of a breast cancer metastasis can determine its sensitivity to available drugs. The testing of our hypothesis could lead to more effective therapeutic strategies – those that are tailored to the location of the metastases. Optimizing therapy in such a way should improve the efficacy of available therapies leading to increased overall survival time of patients with breast cancer.