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Cancer Res. 2016 Mar 1;76(5):1284-96. doi: 10.1158/0008-5472.CAN-15-2478. Epub 2016 Jan 12.

EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas.
3
Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
4
Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington.
5
Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical, University, Taichung, Taiwan. Genomics Research Center, Academia Sinica, Taipei, Taiwan.
6
Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical, University, Taichung, Taiwan.
7
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
8
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas. Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical, University, Taichung, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan. mhung@mdanderson.org.

Abstract

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. 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 EGFR, thereby increasing lactate excretion, which leads to inhibition of local cytotoxic T-cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-d-glucose 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.

PMID:
26759242
PMCID:
PMC4775355
[Available on 2017-03-01]
DOI:
10.1158/0008-5472.CAN-15-2478
[Indexed for MEDLINE]
Free PMC Article

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