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      Inhibition of FASN and ERα signalling during hyperglycaemia-induced matrix-specific EMT promotes breast cancer cell invasion via a caveolin-1-dependent mechanism

      research-article
      a , , a , b , a
      Cancer Letters
      Elsevier Science Ireland
      Breast cancer, Warburg effect, Hyperglycaemia, Epithelial to mesenchymal transition, Fibronectin, ECM, Extracellular matrix, EMT, Epithelial to mesenchymal transition, ERα, Estrogen receptor α, FASN, Fatty acid synthase, GFPT1, Glutamine–fructose-6 phosphateransaminase 1, GLUT, Glucose transporter, G6PD, Glucose-6-phosphate dehydrogenase, LDH, Lactate dehydrogenase, MCT, Monocarboxylate transporter, MET, Mesenchymal to epithelial transition, MMP, Matrix metalloproteinase, NS, Non-silencing, ns, not significant, OXPHOS, Oxidative phosphorylation, PARP, Poly(ADP-ribose) polymerase, PHGDH, Phosphoglycerate dehydrogenase, TALDO1, Transaldolase 1, TCA, tricarboxylic acid, TGFβ, Transforming growth factor β, TKT, Transketolase

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          Abstract

          Since disturbed metabolic conditions such as obesity and diabetes can be critical determinants of breast cancer progression and therapeutic failure, we aimed to determine the mechanism responsible for their pro-oncogenic effects. Using non-invasive, epithelial-like ERα-positive MCF-7 and T47D human breast cancer cells we found that hyperglycaemia induced epithelial to mesenchymal transition (EMT), a key programme responsible for the development of metastatic disease. This was demonstrated by loss of the epithelial marker E-cadherin together with increases in mesenchymal markers such as vimentin, fibronectin and the transcription factor SLUG, together with an enhancement of cell growth and invasion. These phenotypic changes were only observed with cells grown on fibronectin and not with those plated on collagen. Analyzing metabolic parameters, we found that hyperglycaemia-induced, matrix-specific EMT promoted the Warburg effect by upregulating glucose uptake, lactate release and specific glycolytic enzymes and transporters. We showed that silencing of fatty acid synthase (FASN) and the downstream ERα, which we showed previously to mediate hyperglycaemia-induced chemoresistance in these cells, resulted in suppression of cell growth: however, this also resulted in a dramatic enhancement of cell invasion and SLUG mRNA levels via a novel caveolin-1-dependent mechanism.

          Highlights

          • Exposure to hyperglycaemia and fibronectin induced EMT and promoted the Warburg effect in ERα-positive breast cancer cells.

          • Inhibition of the FASN/ERα signalling pathway resulted in a dramatic enhancement of cell invasion.

          • Caveolin-1 mediated the pro-invasive phenotype triggered by targeting FASN or the ERα.

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          Most cited references36

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          New aspects of the Warburg effect in cancer cell biology.

          Altered cellular metabolism is a defining feature of cancer [1]. The best studied metabolic phenotype of cancer is aerobic glycolysis--also known as the Warburg effect--characterized by increased metabolism of glucose to lactate in the presence of sufficient oxygen. Interest in the Warburg effect has escalated in recent years due to the proven utility of FDG-PET for imaging tumors in cancer patients and growing evidence that mutations in oncogenes and tumor suppressor genes directly impact metabolism. The goals of this review are to provide an organized snapshot of the current understanding of regulatory mechanisms important for Warburg effect and its role in tumor biology. Since several reviews have covered aspects of this topic in recent years, we focus on newest contributions to the field and reference other reviews where appropriate. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition

            Metastatic progression, including extravasation and micro-metastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFβ1) induced Epithelial-to-Mesenchymal Transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Over-expressed Snail1, a transcription factor mediating TGFβ1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knock-down was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFβ1-induced EMT and metastasis.
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              Caveolin-1 in tumor progression: the good, the bad and the ugly.

              Caveolin-1 (Cav1) is a multifunctional scaffolding protein with multiple binding partners that is associated with cell surface caveolae and the regulation of lipid raft domains. Cav1 regulates multiple cancer-associated processes including cellular transformation, tumor growth, cell migration and metastasis, cell death and survival, multidrug resistance and angiogenesis. However, Cav1 has been reported to impact both positively and negatively on various aspects of tumor progression and while reported to function as a tumor suppressor, it has also been identified as a poor prognostic factor in various human cancers. In this review, we survey the functional roles of Cav1 in cancer and argue that Cav1 function is interdependent on tumor stage and the expression of molecular effectors that impact on its role during tumor progression.
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                Author and article information

                Contributors
                Journal
                Cancer Lett
                Cancer Lett
                Cancer Letters
                Elsevier Science Ireland
                0304-3835
                1872-7980
                10 April 2018
                10 April 2018
                : 419
                : 187-202
                Affiliations
                [a ]IGFs & Metabolic Endocrinology Group, School of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 5NB, UK
                [b ]Department of Clinical Oncology, Bristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK
                Author notes
                []Corresponding author. Hanna.Zielinska@ 123456bristol.ac.uk
                Article
                S0304-3835(18)30050-8
                10.1016/j.canlet.2018.01.028
                5832758
                29331414
                49bef72c-c199-4cd5-a887-f18e46c7dfb7
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 25 October 2017
                : 25 December 2017
                : 8 January 2018
                Categories
                Article

                Oncology & Radiotherapy
                breast cancer,warburg effect,hyperglycaemia,epithelial to mesenchymal transition,fibronectin,ecm, extracellular matrix,emt, epithelial to mesenchymal transition,erα, estrogen receptor α,fasn, fatty acid synthase,gfpt1, glutamine–fructose-6 phosphateransaminase 1,glut, glucose transporter,g6pd, glucose-6-phosphate dehydrogenase,ldh, lactate dehydrogenase,mct, monocarboxylate transporter,met, mesenchymal to epithelial transition,mmp, matrix metalloproteinase,ns, non-silencing,ns, not significant,oxphos, oxidative phosphorylation,parp, poly(adp-ribose) polymerase,phgdh, phosphoglycerate dehydrogenase,taldo1, transaldolase 1,tca, tricarboxylic acid,tgfβ, transforming growth factor β,tkt, transketolase

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