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, Shannon; 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; Şahin, Ayşegül; Hanash, Samir M.; Hortobágyi, Gabriel N.; Hung, Mien Chie

doi:10.1158/0008-5472.can-15-2478

Cited by 207 publications

(178 citation statements)

References 49 publications

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“…However, the use of this medium introduces challenges in the interpretation of metabolome results because the metabolites that are influenced by these supplements cannot easily be distinguished from those produced endogenously. For instance, EGF signaling is known to activate glycolysis [19]. For this reason, we chose RPMI-1640 medium for suspension cultures.…”

Section: Discussionmentioning

confidence: 99%

Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle

et al. 2016

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The Warburg effect is a metabolic hallmark of cancer cells; cancer cells, unlike normal cells, exclusively activate glycolysis, even in the presence of enough oxygen. On the other hand, intratumoral heterogeneity is currently of interest in cancer research, including that involving cancer stem cells (CSCs). In the present study, we attempted to gain an understanding of metabolism in CSCs that is distinct from that in non-CSCs. After forming spheroids from the OVTOKO (ovarian clear cell adenocarcinoma) and SiHa (cervical squamous cell carcinoma) cell lines, the metabolites of these cells were compared with the metabolites of cancer cells that were cultured in adherent plates. A principle components analysis clearly divided their metabolic features. Amino acids that participate in tricarboxylic acid (TCA) cycle reactions, such as serine and glutamine, were significantly increased in the spheroids. Indeed, spheroids from each cell line contained more total adenylates than did their corresponding cells in adherent cultures. This study demonstrated that cancer metabolism is not limited to aerobic glycolysis (i.e. the Warburg effect), but is flexible and context-dependent. In addition, activation of TCA cycles was suggested to be a metabolic feature of CSCs that was distinct from non-CSCs. The amino acid metabolic pathways discussed here are already considered as targets for cancer therapy, and they are additionally proposed as potential targets for CSC treatment.

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Section: Discussionmentioning

confidence: 99%

Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle

et al. 2016

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“…In TNBC, metabolic dysregulation is driven by factors such as glutathione S-transferase Pi 1 (GSTP1), forkhead box O 3a (FOXO3a), and EGFR-induced c-Myc (43–45). Specifically, c-Myc represses thioredoxin-interacting protein (TXNIP), an inhibitor of glycolytic gene expression and glucose uptake (46).…”

Section: Breast-to-brain Metastasesmentioning

confidence: 99%

Metabolic advantages and vulnerabilities in brain metastases

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Jandial

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2017

Clin Exp Metastasis

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Metabolic adaptations permit tumor cells to metastasize to and thrive in the brain. Brain metastases continue to present clinical challenges due to rising incidence and resistance to current treatments. Therefore, elucidating altered metabolic pathways in brain metastases may provide new therapeutic targets for the treatment of aggressive disease. Due to the high demand for glucose in the brain, increased glycolytic activity is favored for energy production. Primary tumors that undergo Warburg-like metabolic reprogramming become suited to growth in the brain microenvironment. Indeed, elevated metabolism is a predictor of metastasis in many cancer subtypes. Specifically, metabolic alterations are seen in primary tumors that are associated with the formation of brain metastases, namely breast cancer, lung cancer, and melanoma. Because of this selective pressure, inhibitors of key metabolic factors may reduce tumor cell viability, thus exploiting metabolic pathways for cancer therapeutics. This review summarizes the metabolic advantages and vulnerabilities of brain metastases.

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“…2,3 The gene amplification of EGFR accounted for 6% of BC and is related to its increased protein expression. 4 EGFR is a transmembrane receptor tyrosine kinase. It is activated by epithelial growth factor (EGF) and subsequently induces tyrosine kinase activity in the intracellular domain by triggering dimerization; the downstream signal transduction pathways are subsequently activated to complete the transmembrane signal transduction process.…”

Section: Introductionmentioning

confidence: 99%

Increased Eps15 homology domain 1 and RAB11FIP3 expression regulate breast cancer progression via promoting epithelial growth factor receptor recycling

et al. 2017

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Recent research indicates that the C-terminal Eps15 homology domain 1 is associated with epithelial growth factor receptormediated endocytosis recycling in non-small-cell lung cancer. The aim of this study was to determine the clinical significance of Eps15 homology domain 1 gene expression in relation to phosphorylation of epithelial growth factor receptor expression in patients with breast cancer. Primary breast cancer samples from 306 patients were analyzed for Eps15 homology domain 1, RAB11FIP3, and phosphorylation of epithelial growth factor receptor expression via immunohistochemistry. The clinical significance was assessed via a multivariate Cox regression analysis, Kaplan-Meier curves, and the log-rank test. Eps15 homology domain 1 and phosphorylation of epithelial growth factor receptor were upregulated in 60.46% (185/306) and 53.92% (165/306) of tumor tissues, respectively, as assessed by immunohistochemistry. The statistical correlation analysis indicated that Eps15 homology domain 1 overexpression was positively correlated with the increases in phosphorylation of epithelial growth factor receptor (r = 0.242, p < 0.001) and RAB11FIP3 (r = 0.165, p = 0.005) expression. The multivariate Cox proportional hazard model analysis demonstrated that the expression of Eps15 homology domain 1 alone is a significant prognostic marker of breast cancer for the overall survival in the total, chemotherapy, and human epidermal growth factor receptor 2 (−) groups. However, the use of combined expression of Eps15 homology domain 1 and phosphorylation of epithelial growth factor receptor markers is more effective for the disease-free survival in the overall population, chemotherapy, and human epidermal growth factor receptor 2 (−) groups. Moreover, the combined markers are also significant prognostic markers of breast cancer in the human epidermal growth factor receptor 2 (+), estrogen receptor (+), and estrogen receptor (−) groups. Eps15 homology domain 1 has a tumor suppressor function, and the combined marker of Eps15 homology domain 1/phosphorylation of epithelial growth factor receptor expression was identified as a better prognostic marker in breast cancer diagnosis. Furthermore, RAB11FIP3 combines with Eps15 homology domain 1 to promote the endocytosis recycling of phosphorylation of epithelial growth factor receptor. KeywordsBreast cancer, Eps15 homology domain 1, phosphorylation of epithelial growth factor receptor, RAB11FIP3, prognosis Date

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

Cited by 207 publications

References 49 publications

Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle

Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle

Metabolic advantages and vulnerabilities in brain metastases

Increased Eps15 homology domain 1 and RAB11FIP3 expression regulate breast cancer progression via promoting epithelial growth factor receptor recycling

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