Innate immunity gene Nod2 protects mice from orthotopic breast cancer.

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.