Abstract 2271: Peptidylarginine deiminase 2 as a novel therapeutic target for breast cancer

Abstract

Abstract Peptidylarginine deiminases (PADIs) enzymes are calcium-dependent enzymes that post-translationally convert positively charged protein arginine residues to a neutrally charged citrulline in a process known as citrullination or deimination. This loss of charge can alter the tertiary structure of proteins and affect protein-protein and protein-DNA interactions. We, and others, have found that PADI-mediated histone tail citrullination alters chromatin structure and regulates gene expression. For example, we found that PADI2 interacts with estrogen receptor (ERα) and that PADI2-mediated citrullination of histone H3 arginine 26 residues at ERα binding sites regulates target gene expression. In addition, we also found that PADI2 is often co-expressed with HER2 in both breast cancer cell lines and in tumor tissue. Our molecular studies suggest that PADI2 activates HER2 expression via histone citrullination at the HER2 gene locus and that HER2 signaling appears to induce PADI2 expression, thus potentially forming an oncogenic positive feedback loop with HER2. These findings suggest an important role for PADI2 in breast cancer progression. This prediction is supported by our finding that PADI2 expression is upregulated in cancer cells and that depletion of PADI2 from breast cancer cells results in reduced tumorigenicity. In addition, we found that transgenic overexpression of PADI2 promotes carcinogenesis and that the PADI inhibitor, Cl-Amidine, slows tumor growth in mouse models of breast cancer. Furthermore, we found that Cl-Amidine also maintains basement membrane integrity in xenograft tumors, preventing initiation of metastasis. Together, these findings suggest that PADI2 represents a novel therapeutic target and biomarker for early stage breast cancer. Citation Format: Sachi Horibata, John L. McElwee, David Sadegh, Katherine Rogers, Dalton McLean, Scott A. Coonrod. Peptidylarginine deiminase 2 as a novel therapeutic target for breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2271. doi:10.1158/1538-7445.AM2015-2271