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

Seung Oe Lim, Chia Wei Li, Weiya Xia, Heng Huan Lee, Shih Shin Chang, Jia Shen, Jennifer L. Hsu, Daniel Raftery, Danijel Djukovic, Haiwei Gu, Wei Chao Chang, Hung Ling Wang, Mong Liang Chen, Longfei Huo, Chung Hsuan Chen, Yun Wu, Aysegul Sahin, Samir M. Hanash, Gabriel N. Hortobagyi, Mien Chie Hung

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1284-1296
Number of pages13
JournalCancer Research
Volume76
Issue number5
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

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Triple Negative Breast Neoplasms
Tumor Escape
Glycolysis
Growth
Epidermal Growth Factor
Neoplasms
T-Lymphocytes
Immunologic Monitoring
Deoxyglucose
Oncogenes
Lactic Acid
Cell Proliferation
fructose-1,6-diphosphate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

EGFR signaling enhances aerobic glycolysis in triple-negative breast cancer cells to promote tumor growth and immune escape. / Lim, Seung Oe; Li, Chia Wei; Xia, Weiya; Lee, Heng Huan; Chang, Shih Shin; Shen, Jia; Hsu, Jennifer L.; Raftery, Daniel; Djukovic, Danijel; Gu, Haiwei; Chang, Wei Chao; Wang, Hung Ling; Chen, Mong Liang; Huo, Longfei; Chen, Chung Hsuan; Wu, Yun; Sahin, Aysegul; Hanash, Samir M.; Hortobagyi, Gabriel N.; Hung, Mien Chie.

In: Cancer Research, Vol. 76, No. 5, 01.03.2016, p. 1284-1296.

Research output: Contribution to journalArticle

Lim, SO, Li, CW, Xia, W, Lee, HH, Chang, SS, Shen, J, Hsu, JL, Raftery, D, Djukovic, D, Gu, H, Chang, WC, Wang, HL, Chen, ML, Huo, L, Chen, CH, Wu, Y, Sahin, A, Hanash, SM, Hortobagyi, GN & Hung, MC 2016, 'EGFR signaling enhances aerobic glycolysis in triple-negative breast cancer cells to promote tumor growth and immune escape', Cancer Research, vol. 76, no. 5, pp. 1284-1296. https://doi.org/10.1158/0008-5472.CAN-15-2478
Lim, Seung Oe ; Li, Chia Wei ; Xia, Weiya ; Lee, Heng Huan ; Chang, Shih Shin ; Shen, Jia ; Hsu, Jennifer L. ; Raftery, Daniel ; Djukovic, Danijel ; Gu, Haiwei ; Chang, Wei Chao ; Wang, Hung Ling ; Chen, Mong Liang ; Huo, Longfei ; Chen, Chung Hsuan ; Wu, Yun ; Sahin, Aysegul ; Hanash, Samir M. ; Hortobagyi, Gabriel N. ; Hung, Mien Chie. / EGFR signaling enhances aerobic glycolysis in triple-negative breast cancer cells to promote tumor growth and immune escape. In: Cancer Research. 2016 ; Vol. 76, No. 5. pp. 1284-1296.
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AU - Chang, Shih Shin

AU - Shen, Jia

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AU - Gu, Haiwei

AU - Chang, Wei Chao

AU - Wang, Hung Ling

AU - Chen, Mong Liang

AU - Huo, Longfei

AU - Chen, Chung Hsuan

AU - Wu, Yun

AU - Sahin, Aysegul

AU - Hanash, Samir M.

AU - Hortobagyi, Gabriel N.

AU - Hung, Mien Chie

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