Inducible Expression of FGF-3 in Mouse Mammary Gland

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-08, Vol.99 (17), p.11187-11192
• Main Authors: Elly S. W. Ngan, Ma, Zhi-Qing, Chua, Steven S., DeMayo, Francesco J., Tsai, Sophia Y.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Breasts; Cell Adhesion Molecules - genetics; Cell growth; Cellular biology; Cyclins; Disease Progression; Epithelial cells; Epithelial Cells - physiology; Epithelium; Estrogens; Female; Fibroblast Growth Factor 3; Fibroblast Growth Factors - genetics; Gene Expression Regulation, Developmental - physiology; Hormones; Hyperplasia; Mammary glands; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - pathology; Mice; Mice, Transgenic; Mifepristone - pharmacology; Ovariectomy; Placebos; Pregnancy; Proto-Oncogene Proteins - genetics; Rodents; Sexual Maturation; Transgenic animals; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.172366199

Fibroblast growth factor-3 (FGF-3) is a crucial developmental regulator. Aberrant activation of this gene by mouse mammary tumor virus insertion results in pregnancy-responsive mammary tumorigenesis. To characterize better FGF-3 function in postnatal mammary gland development and cancer initiation/progression, we used a mifepristone (RU486)-inducible regulatory system to express conditionally FGF-3 in the mammary epithelium of transgenic mice. Ectopic overexpression of FGF-3 in pubescent mammary glands elicited severe perturbations in early mammary gland development leading to mammary hyperplasia. Ductal elongation was retarded, multiple cysts persisted in the virgin ducts, and ductal epithelium was expanded and multilayered. The altered ductal architecture and the persistence of hyperplastic multilayered epithelium reflect a defect in growth regulation, which resulted from an imbalance between mitogenic and apoptotic signals. By altering the duration of RU486 treatment, we showed that the persistence of mitogenic signal elicited by FGF-3 is crucial for the initiation, progression, and maintenance of the hyperplastic characteristic of the mammary epithelium. The manifestations elicited by FGF-3 could be reversed by RU486 withdrawal. In addition, synergism between the stimulus from estrogen and FGF-3 mitogenic pathways was evident and likely contributes to the pregnancy-dependent tumorigenesis of FGF-3. Taken together, the mifepristone-inducible regulatory system provides a powerful means for understanding the diverse roles of FGF-3 and its interactions with hormones in mammary gland tumorigenesis.