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Innate Immune Inflammatory Response against Enteric Bacteria Helicobacter hepaticus Induces Mammary Adenocarcinoma in Mice

¹ Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts; ² Immunology Research Division, Department of Pathology, Brigham and Women's Hospital; Division of Emergency Medicine, Children's Hospital, Boston, Massachusetts; and ³ Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

Requests for reprints: Susan E. Erdman, Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139. Phone: 617-252-1804; Fax: 617-258-5708; E-mail: serdman{at}mit.edu.

Inflammation associated with bacterial infections is a risk factor for cancers in humans, yet its role in breast cancer remains poorly understood. We have previously shown that innate immune inflammatory response against intestinal bacteria is sufficient to induce colon cancer. Here we report that infecting Rag2-deficient C57BL/6 Apc^Min/+ mice with an intestinal bacterial pathogen, Helicobacter hepaticus, significantly promotes mammary carcinoma in females and enhances intestinal adenoma multiplicity by a tumor necrosis factor (TNF)–dependent mechanism. The mammary and intestinal tumor development as well as the increase in proinflammatory mediators is suppressed by adoptive transfer of interleukin 10–competent CD4⁺CD45RB^loCD25⁺ regulatory (T_R) cells. Furthermore, prior exposure of donor mice to H. hepaticus significantly enhances antitumor potency of their T_R cells. Interestingly, these microbially experienced T_R cells suppress tumorigenesis more effectively in recipient mice irrespective of their tumor etiology. These data suggest that infections with enteric pathogens enhance T_R-cell potency and protect against epithelial cancers later in life, potentially explaining paradoxical increases in cancer risk in developed countries having more stringent hygiene practices. The possibility that dysregulated gut microbial infections in humans may lead to cancer in anatomically distant organs, such as breast, highlights the need for novel immune-based strategies in cancer prevention and treatment. (Cancer Res 2006;66(15):7395-400)