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Cold‐Inducible RNA Binding Protein (CIRP) Decreases Inflammation and Breast Tumor Growth

RNA binding proteins (RBPs) post‐transcriptionally regulate gene expression by associating with the regulatory sequences in the untranslated regions of mRNAs. RBPs are often disrupted in cancer, but current knowledge of their role in regulating cancer‐associated genes is largely based on in vitro studies. Cold‐inducible RBP (CIRP) is a stress‐induced RBP that was recently shown to modulate inflammation in response to cellular stress. CIRP expression is altered in several cancers, including breast cancer. The effect of CIRP on inflammation in breast cancer is not known. This study tested the hypothesis, based on our preliminary data and published studies that CIRP changes the inflammatory profile of breast tumors from pro‐ to anti‐tumorigenic, and that CIRP expression and this altered inflammatory milieu are associated with lower tumorgenicity. To test this hypothesis a transgenic mouse overexpressing CIRP in the mammary epithelium was crossed with the PyMT mouse model of breast cancer. Effects on both early (7‐week‐old mice) and late (14‐week‐old mice) tumorigenesis and inflammation were assessed in CIRP/PyMT and PyMT mice. Mammary glands from 7‐week‐old CIRP/PyMT mice had 50% fewer mammary intraepithelial neoplasias than PyMT mice while 14 week‐old CIRP/PyMT mice had slower tumor growth kinetics, smaller tumors, decreased tumor burden and decreased pulmonary metastasis compared to PyMT mice. Importantly, CIRP protein level correlated with decreased tumorigenesis in CIRP/PyMT mice. To assess effects on the inflammatory environment, mammary glands from 7 and 14‐week‐old mice were incubated in medium overnight and Luminex cytokine assays were performed on the medium. Luminex assays were also performed on sera from 14‐wk mice to assess effects on systemic inflammation. There was a decrease in cytokines that promote inflammation, angiogenesis and metastasis at both timepoints for mammary glands, and in 14‐week sera. Overall, these data support a role for CIRP as a potent anti‐tumor molecule that suppresses local and systemic pro‐tumorigenic inflammation. To begin to probe whether CIRP's effects on cytokine levels were cell‐autonomous, we performed in silico analysis of CIRPs binding affinity for individual targets using the web‐based beRBP tool (Yu et al.). CIRP was not predicted to bind the cytokine mRNAs so may be acting in a non‐cell autonomous fashion.