Transgenie Mice Reveal Roles for TGFα and EGF Receptor in Mammary Gland Development and Neoplasia

Transforming growth factor-alpha (TGF alpha)(4) and/or the EGF receptor (EGFR) are frequently overexpressed by human and rodent breast tumors, as well as tumor-derived cell lines. Additionally, various observations suggest a role for TGF alpha and the EGFR signaling system in normal mouse mammary gland development. Recently, several laboratories have established TGF alpha transgenic mice with which to study the role of this growth factor in normal and neoplastic mammary biology. Examination of these mice revealed that overexpression of TGF alpha has profound consequences for this tissue. Most strikingly, transgenic mice expressing TGF alpha under the control of tissue-specific and nonspecific promoters stochastically developed focal mammary tumors with an incidence and latency that was markedly affected by pregnancy. Most TGF alpha-induced tumors were well-differentiated adenomas/adenocarcinomas, although some were undifferentiated and locally invasive. Distant metastases were only occasionally observed. Administration of the genotoxic carcinogen, 7,12-dimethylbenzanthracene (DMBA), dramatically accelerated mammary tumorigenesis induced by the TGF alpha transgene, raising the possibility that TGF alpha acts as a promoter in this tissue. Mice harboring dual transgenes encoding TGF alpha and either wild-type ERBB2 or c-myc displayed markedly accelerated tumorigenesis compared to mice carrying any of the single transgenes alone, indicative of potent cooperativity. Moreover, tumorigenesis in the bitransgenic mice was less dependent on pregnancy, and tumors were generally more malignant in appearance. Finally, TGF alpha also affected mammary gland dynamics. TGF alpha transgenie mice consistently displayed precocious alveolar development, were variably impaired with respect to lactation, and showed markedly reduced postlactional involution. As a result, the glands of multiparous females accumulated hyperplastic lesions that generally resembled milk-producing alveoli. Limited data support the hypothesis that these lesions were precursors to TGF alpha-induced tumors. In summary, these various findings underscore the potential importance of TGF alpha for cellular differentiation and transformation in the mammary gland. They also establish TGF alpha transgenic mice as a powerful model with which to study the role of EGFR signaling molecules in this dynamic tissue.