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 D1 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 postlactational survival of differentiated epithelium. They also provide evidence of a potent tumorigenic collaboration between TGF-α and c-myc in mammary epithelium.