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Sustained mammary gland‐directed, ponasterone A‐inducible expression in transgenic mice
Author(s) -
Albanese Chris,
Reutens Anne T.,
Bouzahzah Boumediene,
Fu Maofu,
D'Amico Mark,
Link Todd,
Nicholson Robert,
Depinho Ronald A.,
Pestell Richard G.
Publication year - 2000
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.14.7.877
Subject(s) - transgene , biology , mammary gland , genetically modified mouse , enhancer , microbiology and biotechnology , gene expression , gene , cancer research , genetics , cancer , breast cancer
The ability to regulate temporal‐ and spatial‐specific expression of target genes in transgenic mice will facilitate analysis of gene function and enable the generation of murine models of human diseases. The genetic analysis of mammary gland tumorigenesis requires the development of mammary gland‐specific transgenics, which are tightly regulated throughout the adult mammary epithelium. Analysis of genes implicated in mammary gland tumorigenesis has been hampered by mosaic transgene expression and the findings that homozygous deletion of several candidate genes (cyclin D1, Stat5A, prolactin receptor) abrogates normal mammary gland development. We describe the development of transgenic mouse lines in which sustained transgene expression was inducibly regulated, both specifically and homogeneously, in the adult mammary gland epithelium. Transgenes encoding RXRα and a chimeric ecdysone receptor under control of a modified MMTV‐LTR, which targets mammary gland expression, were used. These trans‐genic ‘receptor’ lines were crossed with transgenic ‘enhancer’ lines in which the ecdysone/RXR binding site induced ligand‐dependent expression of trans‐genic β‐galactosidase. Pharmacokinetic analysis of a highly bioactive ligand (ponasterone A), identified through screening ecdysteroids from local plants, demonstrated sustained release and transgene expression in vivo. This transgenic model with both tightly regulated and homogeneous transgene expression, which was sustained in vivo using ligands readily extracted from local flora, has broad practical applicability for genetic analysis of mammary gland disease.—Albanese, C., Reutens, A. T., Bouza‐hzah, B., Fu, M., D'amico, M., Link, T., Nicholson, R., Depinho, R. A., Pestell, R. G. Sustained mammary gland‐directed, ponasterone A‐inducible expression in transgenic mice. FASEB J. 14, 877–884 (2000)