title: Prolonged extracellular signal-regulated kinase 1/2 activation during fibroblast growth factor 1- or heregulin beta1-induced antiestrogen-resistant growth of breast cancer cells is resistant to mitogen-activated protein/extracellular regulated kinase kinase inhibitors.
abstract: Increased growth factor receptor signaling is implicated in antiestrogen-resistant breast tumors suggesting that abrogation of such signaling could restore or prolong sensitivity to antihormonal agents. Activation of the mitogen-activated protein/extracellular regulated kinase kinase (MEK)-extracellular regulated kinase (ERK)1/2 cascade is a common component of such pathways. We investigated the ability of the MEK activation inhibitor U0126 to block the increased growth of estrogen receptor-positive MCF-7 breast cancer cells caused by fibroblast growth factor 1 (FGF-1), heregulin beta1 (HRGbeta1), and epidermal growth factor (EGF) in the presence of the pure antiestrogen ICI 182780 (Faslodex; fulvestrant). We found that either FGF-1 or HRGbeta1 but not EGF substantially reduced the inhibitory effects of U0126 on growth and ERK1/2 activation, including the combined inhibitory effects of U0126 and ICI 182780. FGF-1 and HRGbeta1 also reduced the inhibition of ERK1/2 phosphorylation by the MEK inhibitors PD98059 and PD184161. Interestingly, a transiently transfected dominant-negative MEK1 completely abrogated activation of a coexpressed green fluorescent protein-ERK2 reporter by all three of the factors. Despite a short-lived activation of Ras and Raf-1 by all three of the growth factors, both FGF-1 and HRGbeta1, unlike EGF, induced a prolonged activation of MEK and ERK1/2 in these cells. Thus, activation of FGF-1- and HRGbeta1-specific signaling causes MEK-dependent prolonged activation of ERK1/2, which is incompletely susceptible to known MEK inhibitors. We also demonstrate that the cytosolic phospholipase A2 inhibitor arachidonyl trifluoro methyl ketone and the pan PKC inhibitor bisindolymaleimide abrogated U0126-resistant phosphorylation of ERK1/2 induced by HRGbeta1 but not by FGF-1. Phosphorylation of ERK5 by all three of the factors was also resistant to U0126 suggesting that its activation is not sufficient to overturn growth inhibition due to diminished ERK1/2 activation. Therefore, therapy combining antiestrogens and MEK inhibitors may be ineffective in some antiestrogen-resistant estrogen receptor-positive breast cancers.
authors.affiliation: Biochemistry and Molecular Biology Department, Drug Discovery Division, Southern Research Institute, University of Alabama at Birmingham Comprehensive Cancer Center, USA.
authors.forename: Jaideep V
authors.initials: JV
authors.lastname: Thottassery
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Sun
authors.forename: Louise
authors.initials: L
authors.lastname: Westbrook
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Rentz
authors.forename: Marina
authors.initials: M
authors.lastname: Manuvakhova
authors.forename: Zhican
authors.initials: Z
authors.lastname: Qu
authors.forename: Shanti
authors.initials: S
authors.lastname: Samuel
authors.forename: Ramanda
authors.initials: R
authors.lastname: Upshaw
authors.forename: Amanda
authors.initials: A
authors.lastname: Cunningham
authors.forename: Francis G
authors.initials: FG
authors.lastname: Kern
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D000077267:Fulvestrant; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020890:Neuregulin-1 / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D018631:ras Proteins / Q000096:biosynthesis
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D020890:Neuregulin-1; D009570:Nitriles; C113580:U 0126; D016220:Fibroblast Growth Factor 1; C087230:heregulin beta1; D000077267:Fulvestrant; D004958:Estradiol; D019908:Proto-Oncogene Proteins c-raf; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins