The overarching goal of this project is to improve our understanding of the mechanisms driving mammary tumor progression and to develop new therapeutic strategies for breast cancer. While drugs targeting estrogen receptor (ER) positive (~75% of all tumors) and HER2 overexpressing (15-20% of all tumors) tumors have shown efficacy in the adjuvant and metastatic settings, de novo and acquired resistance to these agents is common. Therefore, new inhibitors that specifically target these pathways are needed to prevent, delay, or reverse resistance. The peptidylarginine deiminases (PADs or PADIs) are a family of calcium-dependent enzymes that convert arginine residues on target proteins to the non-standard amino acid, citrulline in a process alternatively called citrullination or deimination. We have recently documented a pivotal role for peptidylarginine deiminase (PAD2) as an epigenetic activator of ER target gene expression in breast cancer cells via citrullination of histone H3 arginine 26 residues on ER target gene promoters. We have also found that our PAD inhibitors show potent, anti-tumor effects in vivo. Our ongoing pre-clinical in vitro and animal model studies in this area are further testing the hypothesis that PAD2 plays crucial roles in ER and HER2 signaling and that PAD inhibitors represent a promising new therapeutic approach to prevent disease progression in both ER+ and HER2 amplified tumors.