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Published 13 May 2002. doi:10.1083/jcb.200107119
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© The Rockefeller University Press, 0021-9525/2002/5/703 $5.00
The Journal of Cell Biology, Volume 157, Number 4, May 13, 2002 703-714

Article

 Inducible dimerization of FGFR1 : development of a mouse model to analyze progressive transformation of the mammary gland



Bryan E. Welm1,2, Kevin W. Freeman2,3, Mercy Chen1, Alejandro Contreras1, David M. Spencer2,3 and Jeffrey M. Rosen1,2

1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030
2 Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, TX 77030
3 Department of Immunology, Baylor College of Medicine, Houston, TX 77030

Address correspondence to J.M. Rosen, Dept. of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-6210. Fax: 713-798-8012. E-mail: jrosen{at}faculty.bcm.tmc.edu

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.

Key Words: breast cancer; FGFR; inducible dimerization; mammary gland development; angiogenesis


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