title: Mammary tumorigenesis induced by fibroblast growth factor receptor 1 requires activation of the epidermal growth factor receptor.
abstract: Fibroblast growth factor receptor 1 (FGFR1) is an oncoprotein with known involvement in mammary tumorigenesis. To understand how FGFR1 signaling promotes mammary tumorigenesis, an inducible FGFR1 (iFGFR1) system was created previously. Previous studies have demonstrated that upon iFGFR1 activation in vivo, the epidermal growth factor (EGF) ligands amphiregulin (AREG) and epiregulin (EREG) are upregulated. Both AREG and EREG interact with the EGF receptor (EGFR). Here, we investigated whether the FGFR1-induced increase in AREG and EREG expression might coordinately increase EGFR signaling to promote mammary tumorigenesis. Treatment of mouse mammary epithelial cells with either AREG or EREG conferred a greater migratory potential, increased cellular proliferation and increased extracellular regulated kinase 1/2 (ERK1/2) activation. These effects could be blocked with the EGFR-specific inhibitor erlotinib, suggesting that they are EGFR-dependent. In transgenic mice with iFGFR1 under the control of the mouse mammary tumor virus (MMTV) promoter, iFGFR1 activation also led to increased mammary epithelial cell proliferation that was inhibited with erlotinib. Taken together, these data suggest that AREG and EREG mediate tumorigenic phenotypes by activating EGFR signaling, and that the oncogenic potential of FGFR1 requires EGFR activation to promote mammary tumorigenesis.
authors.affiliation: Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Lindsey K
authors.initials: LK
authors.lastname: Bade
authors.forename: Jodi E
authors.initials: JE
authors.lastname: Goldberg
authors.forename: Hazel A
authors.initials: HA
authors.lastname: Dehut
authors.forename: Majken K
authors.initials: MK
authors.lastname: Hall
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schwertfeger
mesh_terms: D066258:Amphiregulin; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D066260:Epiregulin; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011799:Quinazolines / Q000008:administration & dosage; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011799:Quinazolines; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D051496:Receptor, Fibroblast Growth Factor, Type 1