PAD2 Overexpression in Transgenic Mice Promotes Spontaneous Skin Neoplasia

Abstract

Peptidylarginine deiminase 2 (PAD2/PADI2) has been implicated in various inflammatory diseases and, more recently, cancer. The goal of this study was to test the hypothesis that PAD2 promotes oncogenesis using a transgenic mouse model. We found that about 37% of transgenic mice overexpressing human FLAG-PAD2 downstream of the MMTV-LTR promoter develop spontaneous neoplastic skin lesions. Molecular and histopathologic analyses of the resulting lesions find that they contain increased levels of markers for invasion, inflammation, and epithelial-to-mesenchymal transition (EMT) and that a subset of the lesions progress to invasive squamous cell carcinoma (SCC). We then stably overexpressed FLAG-PAD2 in the human SCC cell line, A431, and found that the PAD2-overexpressing cells were more tumorigenic in vitro and also contained elevated levels of markers for inflammation and EMT. Collectively, these studies provide the first genetic evidence that PAD2 functions as an oncogene and suggest that PAD2 may promote tumor progression by enhancing inflammation within the tumor microenvironment. Cancer Res; 74(21); 6306-17. Ó2014 AACR.

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis

“…In contrast to colorectal cancer, an oncogenic role for PADI2 has been reported in breast cancer and squamous carcinomas (15,16). In a cell culture model for breast cancer progression, PADI2 expression correlated with the transformed phenotype and cells and xenografted tumors were sensitive to Cl-amidine treatment (15).…”

“…In a cell culture model for breast cancer progression, PADI2 expression correlated with the transformed phenotype and cells and xenografted tumors were sensitive to Cl-amidine treatment (15). Mice overexpressing PADI2 in a panel of tissues including skin and mammary epithelia spontaneously developed squamous cell carcinomas in the skin in 37% of the cases but no other tumors (16). In vitro data suggested that overexpression of PADI2 in skin carcinoma cells could favor epithelial-to-mesenchymal transitions and thus increase the cells' migratory capacity (16).…”

“…Mice overexpressing PADI2 in a panel of tissues including skin and mammary epithelia spontaneously developed squamous cell carcinomas in the skin in 37% of the cases but no other tumors (16). In vitro data suggested that overexpression of PADI2 in skin carcinoma cells could favor epithelial-to-mesenchymal transitions and thus increase the cells' migratory capacity (16). In contrast, in colorectal cancer, PADI2 is downregulated and reduced expression in both tumor tissue and adjacent mucosa correlated with reduced survival.…”

“…PADI2 was found upregulated in human HER2-positive breast cancers (15). In mice, overexpression of a PADI2 transgene was sufficient to cause skin tumors (16). It has been proposed that PADIs could contribute to cancer by acting as coactivator of oncogenic transcription factors eliciting tumor-promoting expression programs.…”

Origins of cancer symposium 2015: posttranslational modifications and cancer

“…Dr. Coonrod's lab has shown that PAD2 expression is up-regulated in tamoxifen-resistant breast cancer cells [10]. While they predicted that PAD2 might be a driver of breast cancer, unexpectedly, overexpression of PAD2 in mice by the murine mammary tumor virus promoter led to dysplastic tumors in skin cells, but not in mammary glands [11]. This work suggested that PAD2-driven oncogenesis in the skin was due to increased production of inflammatory cytokines, which were not observed in the mammary epithelium.…”