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.
Inducible dimerization of FGFR1 : development of a mouse model to analyze progressive transformation of the mammary gland
The online version of this article contains supplemental material.
B.E. Welm's present address is Dept. of Anatomy, University of California, San Francisco, San Francisco, CA 94143.
Abbreviations used in this paper: BrdU, 5-bromo-2′-deoxyuridine; ECM, extracellular matrix; FGF, fibroblast growth factor; FGFR, FGF receptor; H&E, hematoxylin and eosin; HA, hemagglutinin; LTR, long terminal repeat; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; MMTV, mouse mammary tumor virus; PR, progesterone receptor; TEB, terminal-end bud; TUNEL, TdT-mediated dUTP-biotin nick end labeling.
Bryan E. Welm, Kevin W. Freeman, Mercy Chen, Alejandro Contreras, David M. Spencer, Jeffrey M. Rosen; Inducible dimerization of FGFR1 : development of a mouse model to analyze progressive transformation of the mammary gland . J Cell Biol 13 May 2002; 157 (4): 703–714. doi: https://doi.org/10.1083/jcb.200107119
Download citation file:
Sign in
Client Account
Sign in via your Institution
Sign in via your InstitutionEmail alerts
Advertisement
Advertisement