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Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Oncogene (2018) | Download Citation

Abstract

Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, currently lacks effective targeted therapy options. Eicosapentaenoic acid (EPA), an omega-3 fatty acid and constituent of fish oil, is a common supplement with anti-inflammatory properties. Although it is not a mainstream treatment, several preclinical studies have demonstrated that EPA exerts anti-tumor activity in breast cancer. However, against solid tumors, EPA as a monotherapy is clinically ineffective; thus, we sought to develop a novel targeted drug combination to bolster its therapeutic action against TNBC. Using a high-throughput functional siRNA screen, we identified Ephrin type-A receptor 2 (EPHA2), an oncogenic cell-surface receptor tyrosine kinase, as a therapeutic target that sensitizes TNBC cells to EPA. EPHA2 expression was uniquely elevated in TNBC cell lines and patient tumors. In independent functional expression studies in TNBC models, EPHA2 gene-silencing combined with EPA significantly reduced cell growth and enhanced apoptosis compared with monotherapies, both in vitro and in vivo. EPHA2-specific inhibitors similarly enhanced the therapeutic action of EPA. Finally, we identified that therapy-mediated apoptosis was attributed to a lethal increase in cancer cell membrane polarity due to ABCA1 inhibition and subsequent dysregulation of cholesterol homeostasis. This study provides new molecular and preclinical evidence to support a clinical evaluation of EPA combined with EPHA2 inhibition in patients with TNBC.

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Data availability

The siRNA synthetic-lethal screen data have been deposited in Gene Expression Omnibus (GEO) with accession number: GSE102057 and GPL23844.

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Acknowledgements

We thank Geoffrey Bartholomeusz from the Department of Experimental Therapeutics at the MD Anderson Cancer Center for his assistance in the development of the high-throughput siRNA synthetic-lethal screen, and Funda Meric-Bernstam from the Department of Investigational Cancer Therapeutics for generously providing the BCX010 tumor line. We also thank Nathanael S. Gray from the Department of Biological Chemistry and Molecular Pharmacology at the Dana-Farber Cancer Institute, Harvard Medical School, for generously providing ALW-II-41-27 for this study, and William Dowhan from the Department of Biochemistry and Molecular Biology at the UTHealth McGovern Medical School for his valuable advice on this project. We also thank Kathryn Hale and Sunita Patterson of the Department of Scientific Publications at MD Anderson Cancer Center for expert editorial assistance.

Author contributions

Conception and design (A.M.T.-A., B.L.E., N.T.U.), development of methodology (A.M.T.-A., H.V., P.Y., B.L.E., N.T.U.), acquisition of data (A.M.T.-A., H.V., Y.Q., L.T., K.R.L., Y.-Y.F., B.L.E.), analysis and interpretation of data (A.M.T.-A., H.V., Y.Q., L.T., K.R.L., Y.-Y.F., B.L.E., N.T.U.), writing, review, and/or revision of the manuscript (A.M.T.-A., H.V., Y.Q., L.T., K.R.L., Y.-Y.F., P.Y., R.S.C., B.L.E., N.T.U.), administrative, technical, or material support (A.M.T.-A., H.V., Y.Q., L.T., K.R.L., Y.-Y.F., B.L.E.), study supervision (B.L.E., N.T.U.).

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Author notes

  1. These authors contributed equally: Bedrich L. Eckhardt, Naoto T. Ueno.

Affiliations

  1. The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    • Angie M. Torres-Adorno
  2. Section of Translational Breast Cancer Research and Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Angie M. Torres-Adorno
    • , Bedrich L. Eckhardt
    •  & Naoto T. Ueno
  3. Department of Biochemistry and Molecular Biology, UTHealth McGovern Medical School, Houston, TX, USA

    • Heidi Vitrac
  4. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Yuan Qi
  5. Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Lin Tan
    •  & Peiying Yang
  6. Department of Integrative Biology and Pharmacology, UTHealth McGovern Medical School, Houston, TX, USA

    • Kandice R. Levental
  7. Program in Integrative Nutrition & Complex Diseases, Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA

    • Yang-Yi Fan
    •  & Robert S. Chapkin

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Conflict of interest

The authors declare that they have no conflict of interest.

Financial support

This work was supported by the Morgan Welch Inflammatory Breast Cancer Research Program, the State of Texas Rare and Aggressive Breast Cancer Research Program, the National Institutes of Health/National Cancer Institute through grants R01CA123318 and P30CA016672 (used the Characterized Cell Line Core, the Flow Cytometry and Cellular Imaging Facility, and the Bioinformatics Shared Resource at MD Anderson Cancer Center), the Cancer Prevention and Research Institute of Texas through grant RP110532-P3 (used MD Anderson’s siRNA Screening Service), and the John Dunn Research Foundation Endowment awarded to William Dowhan.

Corresponding authors

Correspondence to Bedrich L. Eckhardt or Naoto T. Ueno.

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DOI

https://doi.org/10.1038/s41388-018-0569-5