Abstract
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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast / drug effects
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Breast / metabolism*
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Breast / pathology
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Cell Division / drug effects
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Cell Division / physiology
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Cell Polarity / drug effects
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Cell Polarity / physiology
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Cell Transformation, Neoplastic / chemically induced
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Cells, Cultured
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Dimerization
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Disease Models, Animal
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Epithelium / drug effects
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Epithelium / metabolism
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Epithelium / pathology
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Estrogens / metabolism
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Estrogens / pharmacology
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Female
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Fluorescent Antibody Technique
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Mammary Neoplasms, Experimental / chemically induced
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Mammary Neoplasms, Experimental / metabolism*
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Transgenic
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Neoplasm Invasiveness / pathology
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Neoplasm Invasiveness / physiopathology
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Phosphorylation / drug effects
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Progesterone / metabolism
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Progesterone / pharmacology
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Receptor Protein-Tyrosine Kinases / drug effects
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor / drug effects
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Receptors, Fibroblast Growth Factor / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Tacrolimus / metabolism
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Tacrolimus / pharmacology
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Tacrolimus Binding Proteins / genetics
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Tacrolimus Binding Proteins / pharmacology
Substances
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Estrogens
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Receptors, Fibroblast Growth Factor
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Recombinant Fusion Proteins
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Progesterone
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Fgfr1 protein, mouse
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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Tacrolimus Binding Proteins
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tacrolimus binding protein 1B
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Tacrolimus