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

Eric P. Sandgren, Ralph L. Brinster, Joyce A. Schroeder, Ting Hu Qui, David C. Lee, Joyce A. Schroeder, David C. Lee, Richard D. Palmiter

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

Deregulated expression of transforming growth factor α (TGF-α) 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-α 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-α transgene. Nonvirgin female mice in all transgenic lineages developed mammary tumors with 100% incidence but variable latency. Among TGF-α lines, mean survival time correlated with the level of transgene expression, and the average life spans of high-expressing WAP-TGF-α and WAP-c-myc mice were similarly reduced. The majority of TGF-α-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-α- and all c-myc-induced tumors were transplantable, but lung metastases were infrequently observed in all transgenic lines. WAP-TGF-α-induced tumors, in marked contrast to those induced by WAP-c-myc, displayed frequent induction of cyclin Dl mRNA, suggesting that expression of this gene may complement that of TGF-α during mammary tumor development Expression of TGF-α also induced precocious development of pregnant glands and delayed or inhibited mammary involution. As a result, multiparious MT-TGF-α and especially WAP-TGF-α females accumulated large numbers of hyperplastic alveolar nodules that resembled the more differentiated TGF-α-induced tumors. Finally, coexpression of WAP-c-myc and WAP-TGF-α 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-α expression in multistage carcinogenesis, and they suggest that in the mammary gland the mechanism of TGF-α-induced transformation may depend on postrotational survival of differentiated epithelium. They also provide evidence of a potent tumorigenic collaboration between TGF-α and c-myc in mammary epithelium.

Original languageEnglish (US)
Pages (from-to)3915-3927
Number of pages13
JournalCancer Research
Volume55
Issue number17
StatePublished - Sep 1 1995

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Inhibition of Mammary Gland Involution Is Associated with Transforming Growth Factor α but not c-myc-induced Tumorigenesis in Transgenic Mice'. Together they form a unique fingerprint.

Cite this