PAD Enzymes in Female Reproductive Tissues and Cancer Pathogenesis

Increasing clinical evidence now suggests that peptidyl-arginine deiminase (PAD) enzymes, especially PAD4 and possibly PAD2, have important roles in tumor progression. Further linking PADs and cancer are recent findings showing that treatment of cancer cell lines and mouse models of disease with PAD inhibitors significantly suppresses tumor growth and, interestingly, also inflammation. Current functional target proteins for PAD-catalyzed citrullination in cancer include transcription factors, co-regulators, and histones, the latter of which alter gene expression patterns in multiple cancerous cell lines. As the novel relationship between PADs, inflammation, and cancer unfolds, next-generation isozyme-specific PAD inhibitors may have therapeutic potential to regulate both the inflammatory tumor microenvironment and tumor cell growth. In this chapter we first discuss expression patterns of PADs in reproductive tissues, focusing on their endocrine regulation, as this appears to have major implication for expression, catalytic activity, and tumorigenesis. Next, the chapter details our current understanding of the molecular pathophysiological roles of PADs in cancer. Finally, we discuss the evolving role of PADs in inflammation, in the context of tumorigenesis, with discussion of the potential of new isozyme-specific PAD inhibitors to serve as adjuvant therapy for malignancies.