title: Estradiol stimulates glucose metabolism via 6-phosphofructo-2-kinase (PFKFB3).
abstract: Estradiol (E2) administered to estrogen receptor-positive (ER(+)) breast cancer patients stimulates glucose uptake by tumors. Importantly, this E2-induced metabolic flare is predictive of the clinical effectiveness of anti-estrogens and, as a result, downstream metabolic regulators of E2 are expected to have utility as targets for the development of anti-breast cancer agents. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) control glycolytic flux via their product, fructose-2,6-bisphosphate (F26BP), which activates 6-phosphofructo-1-kinase (PFK-1). We postulated that E2 might promote PFKFB3 expression, resulting in increased F26BP and glucose uptake. We demonstrate that PFKFB3 expression is highest in stage III lymph node metastases relative to normal breast tissues and that exposure of human MCF-7 breast cancer cells to E2 causes a rapid increase in [(14)C]glucose uptake and glycolysis that is coincident with an induction of PFKFB3 mRNA (via ER binding to its promoter), protein expression and the intracellular concentration of its product, F26BP. Importantly, selective inhibition of PFKFB3 expression and activity using siRNA or a PFKFB3 inhibitor markedly reduces the E2-mediated increase in F26BP, [(14)C]glucose uptake, and glycolysis. Furthermore, co-treatment of MCF-7 cells with the PFKFB3 inhibitor and the anti-estrogen ICI 182,780 synergistically induces apoptotic cell death. These findings demonstrate for the first time that the estrogen receptor directly promotes PFKFB3 mRNA transcription which, in turn, is required for the glucose metabolism and survival of breast cancer cells. Importantly, these results provide essential preclinical information that may allow for the ultimate design of combinatorial trials of PFKFB3 antagonists with anti-estrogen therapies in ER(+) stage IV breast cancer patients.
authors: From the James Graham Brown Cancer Center, Division of Medical Oncology and Hematology, Department of Medicine, University of Louisville, Louisville, Kentucky 40202.
authors: Yoannis
authors: Y
authors: Imbert-Fernandez
authors: Brian F
authors: BF
authors: Clem
authors: Julie
authors: J
authors: O'Neal
authors: Daniel A
authors: DA
authors: Kerr
authors: Robert
authors: R
authors: Spaulding
authors: Lilibeth
authors: L
authors: Lanceta
authors: Amy L
authors: AL
authors: Clem
authors: Sucheta
authors: S
authors: Telang
authors: Jason
authors: J
authors: Chesney
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005635:Fructosediphosphates / Q000378:metabolism; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008207:Lymphatic Metastasis; D061986:MCF-7 Cells; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D005635:Fructosediphosphates; D000077267:Fulvestrant; D004958:Estradiol; C027652:fructose 2,6-diphosphate; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D005947:Glucose
keywords: Breast Cancer; Estrogen; Estrogen Receptor; Glycolysis; Metabolism; PFKFB3