Inducible dimerization of FGFR1: development of a mouse model to analyze progressive transformation of the mammary gland.
To develop an inducible and progressive model of mammary gland tumorigenesis, transgenic mice were generated with a mouse mammary tumor virus-long terminal repeat-driven, conditional, fibroblast growth factor (FGF)-independent FGF receptor (FGFR)1 (iFGFR1) that can be induced to dimerize with the drug AP20187. Treatment of transgenic mice with AP20187 resulted in iFGFR1 tyrosine phosphorylation, increased proliferation, activation of mitogen-activated protein kinase and Akt, and lateral budding. Lateral buds appeared as early as 3 d after AP20187 treatment and initially consisted of bilayered epithelial cells and displayed apical and basolateral polarity appeared after 13 d of AP20187 treatment. Invasive lesions characterized by multicell-layered lateral buds, decreased myoepithelium, increased vascular branching, and loss of cell polarity were observed after 2-4 wk of treatment. These data indicate that acute iFGFR1 signaling results in increased lateral budding of the mammary ductal epithelium, and that sustained activation induces alveolar hyperplasia and invasive lesions.
Welm
Bryan E
BE
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Freeman
Kevin W
KW
Chen
Mercy
M
Contreras
Alejandro
A
Spencer
David M
DM
Rosen
Jeffrey M
JM
D000818:Animals; D001940:Breast / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019281:Dimerization; D004195:Disease Models, Animal; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000494:pharmacology
D004967:Estrogens; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D011374:Progesterone; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D016559:Tacrolimus