Elucidating The Role Of Peptidylarginine Deiminase 2(Padi2) In Mammary Tumor Progression
Peptidylarginine deiminase 2 (PADI2) post-translationally converts positively charged protein arginine residues to neutrally charged citrulline, a process known as citrullination or deimination. We first demonstrated that PADI2 is expressed in mammary gland and its expression is regulated by estrogen. We and others have also found that PADI2 is often overexpressed in breast cancer. To test the ability of PADI2 to alter the tumorigenic properties of breast cancer cells, we either depleted PADI2 from breast cancer cells or suppressed PADI2 activity using PADI inhibitors. We found that PADI2 depletion or inhibition suppresses cell migration and alters the morphology of breast cancer cells. In vivo, we found that PADI2 overexpression results in mammary gland hyperbranching, a phenotype often observed during carcinogenesis. In addition, we found that inhibition of PADI2 activity with the PADI inhibitor, BB-Cl-Amidine, suppresses EGF-induced ductal invasion in our mammary gland organoid study. Together, our work suggests that PADI2 plays a critical role in breast cancer cell migration and invasion. Our previous transcriptomics studies revealed that PADI2 expression is highly correlated with the expression of the oncogene, HER2, across more than 50 breast cancer cell lines. Thus, we investigated the relationship between PADI2 and HER2. Results show that PADI2 appears to be involved in HER2 signaling, both up and downstream of HER2. We have also demonstrated that PADI2 functions as an estrogen receptor (ER) cofactor by citrullinating histone arginine residues at ER binding sites, thereby promoting stable ER binding and target gene expression. The observation that PADI2 appears to play key roles in both ER and HER2 signaling in breast cancer cells suggests that PADI2 likely plays a critical role in breast cancer progression. The goal of my thesis work was to further investigate the mechanisms by which PADI2 regulates these signal transduction pathways in breast cancer.
Roberson,Mark Stephen; Cerione,Richard A; Weiss,Robert S.
Ph.D. of Pharmacology
Doctor of Philosophy
dissertation or thesis