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      EGFR signaling enhances aerobic glycolysis in triple negative breast cancer cells to promote tumor growth and immune escape

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          Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Epidermal growth factor (EGF) signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGF receptor (EGFR), thereby increasing lactate excretion which leads to inhibition of local cytotoxic T cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC.

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          Author and article information

          Cancer Res
          Cancer Res.
          Cancer research
          9 February 2016
          12 January 2016
          1 March 2016
          01 March 2017
          : 76
          : 5
          : 1284-1296
          [1 ]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
          [2 ]Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
          [3 ]Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
          [4 ]Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
          [5 ]Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
          [6 ]Northwest Metabolomics Center, Department of Anesthesiology and Pain Medicine, University of Washington, Washington 98109, USA
          [7 ]Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
          [8 ]Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404
          [9 ]Genomics Research Center, Academia Sinica, Taipei 115
          [10 ]Department of Biotechnology, Asia University, Taichung 413
          Author notes
          Correspondence should be addressed to Mien-Chie Hung, Department of Molecular and Cellular Oncology, Unit 108, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-3668. Fax: (713) 794-3270. mhung@ 123456mdanderson.org
          PMC4775355 PMC4775355 4775355 nihpa748464


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