Proinflammatory CD4+CD45RBhi lymphocytes promote mammary and intestinal carcinogenesis in ApcMin/+ mice

Cancers of breast and bowel are increasingly frequent in humans. Chronic inflammation is known to he 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 CD4(+)CD45RB(hi) (T-E) cells to induce inflammatory bowel disease (IBD) in mice, to investigate roles of inflammation on carcinogenesis in the Apc(Min/+) mouse model of intestinal polyposis. We find that transfer of T-E cells significantly increases adenoma multiplicity and features of malignancy in recipient Apc(Min/+) mice. Surprisingly, we find that female Apc(Min/+) recipients of T-E cells also rapidly develop mammary tumors. Both intestinal polyposis and mammary adenocarcinoma are abolished by cotransfer of anti-inflaminatory CD4(+)CD45RB(lo) regulatory lymphocytes or by neutralization of key proinflammatory cytokine tumor necrosis factor-alpha. Lastly, down-regulation of cyclooxygenase-2 and c-Myc expression is observed coincident with tumor regression. These findings define a novel mouse model of inflammation-driven mammary carcinoma and suggest that epithelial carcinogenesis can be mitigated by anti-inflammatory cells and cytokines known to regulate IBD in humans and mice.