Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms13007
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Funding
- NIH [CA158055, CA200673, CA203834, R56 AI118719, T32 AI007260, T32 AI007485, R01 AI104706]
- V Scholar award from Holden Comprehensive Cancer Center at the University of Iowa
- American Cancer Society seed grant from Holden Comprehensive Cancer Center at the University of Iowa
- Breast Cancer Research Award from Holden Comprehensive Cancer Center at the University of Iowa
- Oberley Award (National Cancer Institute Award) from Holden Comprehensive Cancer Center at the University of Iowa [P30CA086862]
- Department of Pathology, University of Iowa
- Susan G. Komen for the Cure Promise Grant [KG081048]
- [K22CA118182]
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Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1 beta, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Further studies show that treatment of mice with metformin inhibits obesity-associated tumour progression associated with a marked decrease in angiogenesis. This report provides a causal mechanism by which obesity promotes breast cancer progression and lays out a foundation to block NLRC4 inflammasome activation or IL-1 beta signalling transduction that may be useful for the treatment of obese cancer patients.
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