Abstract
BACKGROUND: Nod2 is involved in innate immune responses to bacteria, regulation of metabolism, and sensitivity to cancer. A Nod2 polymorphism is associated with breast cancer, but the role of Nod2 in the development and progression of breast cancer is unknown. METHODS: Here, we tested the hypothesis that Nod2 protects mice from breast cancer using the 4T1 orthotopic model of mammary tumorigenesis. WT and Nod2(-/-) mice were injected with 4T1 mammary carcinoma cells and the development of tumors was monitored. A detailed analysis of the tumor transcriptome was performed and genes that were differentially expressed and pathways that were predicted to be altered between WT and Nod2(-/-) mice were identified. The activation of key signaling molecules involved in metabolism and development of cancer was studied. RESULTS: Our data demonstrate that Nod2(-/-) mice had a higher incidence and larger tumors than WT mice. Nod2(-/-) mice had increased expression of genes that promote DNA replication and cell division, and decreased expression of genes required for lipolysis, lipogenesis, and steroid biosynthesis compared with WT mice. Nod2(-/-) mice also had lower expression of genes required for adipogenesis and reduced levels of lipids compared with WT mice. The tumors in Nod2(-/-) mice had decreased expression of genes associated with PPARα/γ signaling, increased activation of STAT3, decreased activation of STAT5, and no change in the activation of ERK compared with WT mice. CONCLUSIONS: We conclude that Nod2 protects mice from the 4T1 orthotopic breast tumor, and that tumors in Nod2(-/-) mice are predicted to have increased DNA replication and cell proliferation and decreased lipid metabolism compared with WT mice.