The Interleukin (IL)-1R1 pathway is a critical negative regulator of PyMT-mediated mammary tumorigenesis and pulmonary metastasis

ABSTRACT

Breast cancer is the most common cancer in women and the second leading cause of female cancer-related deaths worldwide. Inflammation is an established hallmark of tumorigenesis and an important determinant of tumor outcome and response to therapy. With advances in cancer immunotherapy, there is an urgent need to dissect the contribution of specific immune effectors in cancer development. Here, we genetically investigated the role of the Interleukin-1 (IL-1) receptor 1 (IL-1R1) pathway in breast cancer tumorigenesis and metastasis using the MMTV-PyMT mouse model. Our results indicate that IL-1R1 signaling suppresses mammary tumor cell proliferation early in tumorigenesis and curbs breast cancer outgrowth and pulmonary metastasis. We show that PyMT/Il1r1^−/− mice had a higher primary tumor burden and increased mortality rate compared with IL-1R1-sufficient PyMT control mice. This phenotype was independent of the inflammatory caspases-1/-11 but driven by IL-1α, as PyMT/Il1a^−/− mice phenocopied PyMT/Il1r1^−/− mice. Collectively, our results suggest that IL-1α-mediated IL-1R1 signaling is tumor-suppressive in PyMT-driven breast cancer.

KEYWORDS:

• Breast cancer
• IL-1R1
• IL-1α
• inflammation
• inflammasome
• proliferation
• tumor suppression

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Dr. Jerry Pelletier for providing PyMT mice on the C57/Bl6 background. We also thank Dr. Yoichiro Iwakura and Dr. Thirumala-Devi Kanneganti for providing Il1a^−/− mice.

Funding

This work was supported by grants from the Canadian Institutes for Health Research (CIHR) and the Burroughs Wellcome Fund to M.S. who is a Fonds de Recherche en Santé du Québec (FRSQ) Senior Investigator and a McGill University William Dawson Scholar. M.D. and J.D. were supported by doctoral awards from the (CIHR), A.M. was supported by a CIHR/CAG/Abbott post-doctoral fellowship and is part of the Mitacs Accelerate program.