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Inhibition of Mammary Gland Involution Is Associated with Transforming Growth Factor but not c-myc-induced Tumorigenesis in Transgenic Mice¹

Laboratory of Reproductive Physiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 [E. P. S., R. L. B.]; Lineberger Comprehensive Cancer Center [J. A. S., T. H. Q., D. C. L.] and Department of Microbiology and Immunology [J. A. S., D. C. L.], University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7295; and Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, Washington 98195 [R. D. P.]

Deregulated expression of transforming growth factor (TGF-) or c-myc has been implicated in the genesis of human breast cancer. To better characterize the role of these molecules in this disease, we generated transgenic mice that express TGF- or c-myc under control of the mouse whey acidic protein (WAP) promoter. We then compared the resulting mammary gland neoplasia in these mice and in previously described mice expressing a metallothionein-driven TGF- transgene. Nonvirgin female mice in all transgenic lineages developed mammary tumors with 100% incidence but variable latency. Among TGF- lines, mean survival time correlated with the level of transgene expression, and the average life spans of high-expressing WAP-TGF- and WAP-c-myc mice were similarly reduced. The majority of TGF--induced tumors were relatively well-differentiated adenomas and adenocarcinomas; in contrast, WAP-c-myc tumors were poorly differentiated, solid carcinomas with a minority of adenocarcinomas. Most TGF-- and all c-myc-induced tumors were transplantable, but lung metastases were infrequently observed in all transgenic lines. WAP-TGF--induced tumors, in marked contrast to those induced by WAP-c-myc, displayed frequent induction of cyclin D1 mRNA, suggesting that expression of this gene may complement that of TGF- during mammary tumor development. Expression of TGF- also induced precocious development of pregnant glands and delayed or inhibited mammary involution. As a result, multiparious MT-TGF- and especially WAP-TGF- females accumulated large numbers of hyperplastic alveolar nodules that resembled the more differentiated TGF--induced tumors. Finally, coexpression of WAP-c-myc and WAP-TGF- transgenes markedly decreased tumor latency, increased tumor growth, and even induced mammary tumors in virgin female and male mice. These findings provide further evidence for the importance of deregulated TGF- expression in multistage carcinogenesis, and they suggest that in the mammary gland the mechanism of TGF--induced transformation may depend on postlactational survival of differentiated epithelium. They also provide evidence of a potent tumorigenic collaboration between TGF- and c-myc in mammary epithelium.

¹ This work was supported by NIH Grants CA43793 and CA61896, American Cancer Society Grant BE-91 (D. C. L.), and NIH Grant CA38635 (R. L. B.).

² Present address: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin at Madison, Madison, WI 53706.

³ To whom requests for reprints should be addressed.

Received 4/18/95. Accepted 7/ 5/95.

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