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Omega-3 fatty acids reduce obesity-induced tumor progression independent of GPR120 in a mouse model of postmenopausal breast cancer

Oncogene volume 34, pages 3504–3513 (2015)Cite this article

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Abstract

Obesity and inflammation are both risk factors for a variety of cancers, including breast cancer in postmenopausal women. Intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of breast cancer, and also reduces obesity-associated inflammation and insulin resistance, but whether the two effects are related is currently unknown. We tested this hypothesis in a postmenopausal breast cancer model using ovariectomized, immune-competent female mice orthotopically injected with Py230 mammary tumor cells. Obesity, whether triggered genetically or by high-fat diet (HFD) feeding, increased inflammation in the mammary fat pad and promoted mammary tumorigenesis. The presence of tumor cells in the mammary fat pad further enhanced the local inflammatory milieu. Tumor necrosis factor-alpha (TNF-α) was the most highly upregulated cytokine in the obese mammary fat pad, and we observed that TNF-α dose-dependently stimulated Py230 cell growth in vitro. An ω-3 PUFA-enriched HFD (referred to as fish oil diet, FOD) reduced inflammation in the obese mammary fat pad in the absence of tumor cells and inhibited Py230 tumor growth in vivo. Although some anti-inflammatory effects of ω-3 PUFAs were previously shown to be mediated by the G-protein-coupled receptor 120 (GPR120), the FOD reduced Py230 tumor burden in GPR120-deficient mice to a similar degree as observed in wild-type mice, indicating that the effect of FOD to reduce tumor growth does not require GPR120 in the host mouse. Instead, in vitro studies demonstrated that ω-3 PUFAs act directly on tumor cells to activate c-Jun N-terminal kinase, inhibit proliferation and induce apoptosis. Our results show that obesity promotes mammary tumor progression in this model of postmenopausal breast cancer and that ω-3 PUFAs, independent of GPR120, inhibit mammary tumor progression in obese mice.

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Acknowledgements

We thank Dr Robert Cardiff for reviewing histologic sections of tumors and Hang Ha and Jonathan Hasselmann for assistance with animal maintenance. We thank the UCSD Histology Core lab for technical assistance with processing the tumor samples. The study was funded in part by the National Institutes of Health grants U54 CA155435, P30 CA23100, P30 DK063491 (JMO), K22 CA118182 (LGE), the Department of Defense grant BC102147 (JMO) and a Doris Howell Foundation Scholarship (JTS).

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Medicine, University of California, La Jolla, CA, USA

    H Chung, Y S Lee, R Mayoral, D Y Oh, N J Webster, D D Sears & J M Olefsky

  2. Biomedical Network Center for the study of Hepatic and Digestive Diseases (CIBERehd), Madrid, Spain

    R Mayoral

  3. Department of Pathology, University of California at San Diego, La Jolla, CA, USA,

    J T Siu & L G Ellies

  4. Moores Cancer Center, University of California, La Jolla, CA, USA

    N J Webster, D D Sears, J M Olefsky & L G Ellies

  5. San Diego VA Healthcare System, San Diego, CA, USA

    N J Webster

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  1. H Chung
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Correspondence to L G Ellies.

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Chung, H., Lee, Y., Mayoral, R. et al. Omega-3 fatty acids reduce obesity-induced tumor progression independent of GPR120 in a mouse model of postmenopausal breast cancer. Oncogene 34, 3504–3513 (2015). https://doi.org/10.1038/onc.2014.283

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