PROJECT SUMMARY Breast cancer is the second leading cause of cancer-related deaths in the US, primarily because breast cancer cells metastasize to vital organs including the brain. Brain metastases, which are refractory to chemotherapy, occur in approximately 15-35% of metastatic breast cancer cases. Current clinical management of brain metastases is limited to radiation therapy and surgical resection and the median survival time for patients is very short. Therefore, better therapeutic strategy against the disease is urgently needed. Emerging evidence suggest that key steps of metastasis are controlled by reversible epigenetic mechanisms, which can be targeted to prevent and treat the disease. Using a systematic in vivo screening approach, I have identified chromobox protein homolog 7 (CBX7) as a candidate suppressor of breast cancer metastasizing to the brain. However, the mechanism of how CBX7 regulates metastasis in the context of breast cancer remains unknown. Thus, I hypothesize that CBX7 plays a suppressive role in breast cancer brain metastasis, and that the process is reversible and can be targeted pharmacologically. The primary goals of this project are to elucidate the molecular mechanisms and biological functions of CBX7 in breast cancer brain metastasis and to develop a novel therapeutic strategy by targeting its downstream signaling pathways. I will test the hypothesis by utilizing mouse models, genomic analyses, and small molecule inhibitors to assess the effect of targeting CBX7-suppressed pathways on preventing and treating brain metastasis. In Aim 1, I will dissect the molecular mechanisms of CBX7 in regulating breast cancer brain metastasis to identify novel CBX7-target genes and pathway(s). In Aim 2, I will perform in vivo experiments to characterize the biological functions of CBX7 in breast cancer brain metastasis. Specifically, I will focus on its roles in the late stage of cancer metastasis and its crosstalk with the brain microenvironment. The completion of this project will reveal a novel epigenetically regulated pathway in cancer metastasis and the brain microenvironment. My proposed project is highly translational as the identified signaling pathway(s) can be rapidly developed into targeted therapies for treating the metastatic diseases.