Novel tumor suppressive role of Peptidylarginine IV involving cancer stem cell regulation in a breast cancer model

Authors

• HJ Ochoa
• N Moshkovich
• B Tang
• LM Wakefield

Abstract

Breast cancer (BC) is a global problem that accounts for over half a million deaths annually. Despite development of therapeutic strategies that can effectively reduce tumor size in neo-adjuvant settings, treated patients often relapse and develop metastasis. Emerging research indicates that a subpopulation of tumorigenic cells capable of self-renewal and drug resistance, termed cancer stem cells (CSCs), drive relapse. Understanding the properties of these CSCs is critical for development of more targeted therapies. Peptidyl arginine deiminase 4 (PADI4) is a protein that catalyzes deimination of arginine to citrulline residues, and citrullination of histones modulates key pluripotency/stemness factors via chromatin decondensation (Christophorou, et al., 2014). Thus, we hypothesized that PADI4 could be involved in CSC regulation. We analyzed PADI4 expression in BC cell lines and determined that luminal BC cells express PADI4 at higher levels than other subtypes. To assess the effect of PADI4 on tumor cell biology, we proceeded with PADI4 knockdown (KD) in the MCF10Ca1h luminal BC model. We demonstrated that PADI4 perturbation does not alter proliferation of the total cell population (CSCs plus non-CSCs) in vitro. However, PADI4 KD increases clonogenicity and induces large tumorsphere formation, indicating that it specifically increased CSC population/activity. Knockdown of PADI4 function also increases migration and invasion despite showing no identifiable morphological differences. In vivo studies showed increased metastatic incidence following PADI4 KD. In conclusion, our findings suggest that PADI4 may function as a tumor suppressor through effects on the CSC, and may be an important inhibitor of metastasis in luminal BC.

Scientific Focus Area: Cancer Biology

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