title: EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape.
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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Seung-Oe
authors.initials: SO
authors.lastname: Lim
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Heng-Huan
authors.initials: HH
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Shih-Shin
authors.initials: SS
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hsu
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Raftery
authors.affiliation: Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington.
authors.forename: Danijel
authors.initials: D
authors.lastname: Djukovic
authors.affiliation: Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Gu
authors.affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical, University, Taichung, Taiwan. Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical, University, Taichung, Taiwan.
authors.forename: Hung-Ling
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical, University, Taichung, Taiwan.
authors.forename: Mong-Liang
authors.initials: ML
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Longfei
authors.initials: L
authors.lastname: Huo
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.affiliation: 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.
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
authors.affiliation: Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: 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.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000332:Aerobiosis; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006019:Glycolysis; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011770:Pyruvate Kinase / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D064726:Triple Negative Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019139:Tumor Escape
chemical_list: D011770:Pyruvate Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors