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Stimulates Proliferation and Apoptosis and Impairs Differentiation in a Transgenic Model1
1 Institute for Pathology, Department of Developmental Pathology, University of Bonn Medical School, Bonn, Germany;
2 Albert Einstein College of Medicine, Bronx, NY; and
3 Forschungszentrum Karlsruhe, Institute for Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany
Requests for reprints: Hubert Schorle, Institute for Pathology, Department of Developmental Pathology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. Phone: 49-228-287-6342; Fax: 49-228-287-9757. E-mail: hubert.schorle{at}ukb.uni-bonn.de
AP-2 transcription factors play pivotal roles in orchestrating embryonic development by influencing the differentiation, proliferation, and survival of cells. Furthermore, AP-2 transcription factors have been implicated in carcinogenesis, a process where the normal growth and differentiation program of cells is disturbed. To experimentally address the potential involvement of AP-2 in mammary gland tumorigenesis, we generated mice overexpressing AP-2
by transgenesis using the mouse mammary tumor virus-long terminal repeat as the transgene-driving promoter unit. In the mammary gland, transgene expression elicited a hyperproliferation that, however, was counterbalanced by the enhanced apoptosis of epithelial cells leading to a hypoplasia of the alveolar epithelium during late pregnancy. In addition, secretory differentiation was impaired, resulting in a lactation failure. In male transgenic mice, the seminal vesicles were sites of strong transgene expression. There the effects of AP-2 on proliferation and apoptosis were even more pronounced, and differentiation was impaired, too, as revealed by the absence of androgen receptor immunoreactivity. In both tissues, the mammary gland and the seminal vesicles, enhanced steady-state transcript levels of the AP-2 target gene IGFBP-5 were detected, revealing a potential mechanism of AP-2-induced apoptosis. Our results suggest a role of AP-2 transcription factors in the maintenance of a proliferative and undifferentiated state of cells, characteristics not only important during embryonic development but also in tumorigenesis.
Key Words: AP-2 • Transcription factor • Transgenic mice • Mammary gland • Tumorigenesis
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