The inhibitory network between EZH2 and PARP1 in triple-negative breast cancer

Breast cancer remains the leading cause of cancer-related death in American women. It is estimated that over 240,000 new breast cancer patients will be diagnosed, and approximately 40,000 patients will die each year in the U.S. Breast cancer is characterized by uncontrolled growth of breast epithelial cells, which can detach, migrate, and invade to other organs causing metastasis. However, the molecular mechanisms of breast cancer are not yet fully understood. One subtype of metastatic breast cancer, triple negative breast cancer (TNBC), is the most aggressive and the most difficult to treat. Therefore, development of new treatments is important in eliminating the mortality and morbidity associated with metastatic breast cancer. Breast cancer develops due to dysregulated gene expression, dysfunctional DNA-damage repair pathways, and is also affected by environmental factors, which epigenetically regulate gene expression and DNA repair pathways. Epigenetic modifiers, such as Polycomb group (PcG) proteins, are crucial in cancer initiation, progression, and metastasis by modifying histones and non-histone proteins. One member of the Polycomb Repressive Complex 2 (PRC2), EZH2, specifically methylates histone H3 protein at lysine 27 to regulate gene expression and is upregulated in invasive breast carcinomas and metastatic breast cancer. High expression levels of EZH2 are strongly associated with poor clinical outcomes in breast cancer patients. The DNA repair protein, PARP1, is also upregulated in breast cancer, but PARP1 inhibitors have been limited to BRCA1 and/or BRCA2 (Breast Cancer 1 or 2)-deficient breast cancer patients (5-10% of all breast cancer cases). EZH2 can actually impair DNA damage repair. However, whether EZH2 and other members of PRC2 regulate PARP1 is unknown. Therefore, the central hypothesis of this proposal is that PRC2 proteins methylate PARP1 lysines, repressing DNA repair activity, and act as PARP1 co-factors in TNBC and the DNA damage response