Proinflammatory CD4CD45RB Lymphocytes Promote Mammary and Intestinal Carcinogenesis in Apc Mice

Cancers of breast and bowel are increasingly frequent in humans. Chronic inflammation is known to be a risk factor for these malignancies, yet cellular and molecular mechanisms linking inflammation and carcinogenesis remain poorly understood. Here, we apply a widely used T-cell transfer paradigm, involving adoptive transfer of proinflammatory CD4CD45RB (TE) cells to induce inflammatory bowel disease (IBD) in mice, to investigate roles of inflammation on carcinogenesis in the Apc mouse model of intestinal polyposis. We find that transfer of TE cells significantly increases adenoma multiplicity and features of malignancy in recipient Apc mice. Surprisingly, we find that female Apc recipients of TE cells also rapidly develop mammary tumors. Both intestinal polyposis and mammary adenocarcinoma are abolished by cotransfer of anti-inflammatory CD4CD45RB regulatory lymphocytes or by neutralization of key proinflammatory cytokine tumor necrosis factor-A. Lastly, down-regulation of cyclooxygenase-2 and c-Myc expression is observed coincident with tumor regression. These findings define a novel mouse model of inflammationdriven mammary carcinoma and suggest that epithelial carcinogenesis can be mitigated by anti-inflammatory cells and cytokines known to regulate IBD in humans and mice. (Cancer Res 2006; 66(1): 57-61)