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Oncogene. 2018 Nov 20. doi: 10.1038/s41388-018-0569-5. [Epub ahead of print]

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

Author information

1
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
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.
3
Department of Biochemistry and Molecular Biology, UTHealth McGovern Medical School, Houston, TX, USA.
4
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
5
Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
Department of Integrative Biology and Pharmacology, UTHealth McGovern Medical School, Houston, TX, USA.
7
Program in Integrative Nutrition & Complex Diseases, Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA.
8
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. beckhardt@mdanderson.org.
9
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. nueno@mdanderson.org.

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.

PMID:
30459358
DOI:
10.1038/s41388-018-0569-5

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