Eric Sinn

Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene

We have used transgenic mice that carry an activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV) promoter to assess the stepwise progression of carcinogenesis in mammary epithelium. Unlike the stochastic occurrence of solitary mammary tumors in transgenic mice bearing the MMTV/c-myc or the MMTV/v-Ha-ras oncogenes, transgenic mice uniformly expressing the MMTV/c-neu gene develop mammary adenocarcinomas that involve the entire epithelium in each gland. Because these tumors arise synchronously and are polyclonal in origin, expression of the activated c-neu oncogene appears to be sufficient to induce malignant transformation in this tissue in a single step. In contrast, expression of the c-neu transgene in the parotid gland or epididymis leads to benign, bilateral epithelial hypertrophy and hyperplasia which does not progress to full malignant transformation during the observation period. These results indicate that the combination of activated oncogene and tissue context are major determinants of malignant progression and that expression of the activated form of c-neu in the mammary epithelium has particularly deleterious consequences.

Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: Synergistic action of oncogenes in vivo

We have derived and mated separate strains of transgenic mice that carry either the v-Ha-ras or the c-myc gene driven by the mouse mammary tumor virus (MMTV) promoter/enhancer. Mice carrying the MMTV/v-Ha-ras transgene manifest two distinct disturbances of cell growth. The first, a benign hyperplasia of the Harderian lacrimal gland, is diffuse, involves the entire gland, and likely requires only the abnormal action of the v-Ha-ras gene. The second involves the focal development of malignancies of mammary, salivary, and lymphoid tissue and likely requires additional somatic events. When the MMTV/v-Ha-ras and MMTV/c-myc strains are crossed to yield hybrid mice, their joint action results in a dramatic and synergistic acceleration of tumor formation. Since these tumors arise stochastically and are apparently monoclonal in origin, additional somatic events appear necessary for their full malignant progression, even in the presence of activated v-Ha-ras and c-myc transgenes.

Mammary Morphogenesis and Oncogenes

The effects of specific oncogenes on the differentiation of the mammary epithelium can now be studied using transgenic animals and glands (1). Many studies have now appeared describing the use of different transgenes and several different promotor systems to produce mammary tumors (1,2). The use of binary systems for tissue-specific promotion of oncogenes and the production of bigenic and trigenic animals through hybrid crosses promise to expand the analysis of different oncogenes in mammary epithelium (3). Some investigators have recognized the presence of various types of mammary hyperplasia and mammary dysplasia in these animals (4,5). However, there has been very little discussion of the growth and development of the mammary gland in these animals and there have been no comparative studies of the effects of different oncogenes on the morphogenesis of the mammary gland. In the following review, we will summarize our collective experience with mammary growth and development and with mammary tumorigenesis in one set of transgenic animals.