Hormonal induction of mammary tumor viruses and its implications for carcinogenesis

The purpose of this study was to evaluate the possibility that hormones and mouse mammary tumor virus (MuMTV) are cocarcinogenic for mammary epithelium. Results of our investigations in vivo and in vitro suggest: (a) Hormones promote mammary carcinogenesis in BALB/c females whether MuMTV is germinally (BALB/c) or horizontally (BALB/cfC3H) transmitted; the rate of carcinogenesis in BALB/cfC3H females is substantially faster than it is in BALB/c, but the final mammary carcinoma incidence is approximately the same. The rate-limiting step in malignant transformation in BALB/c, which infectious MuMTV overcomes, is in premalignant transformation from normal. (b) One characteristic of horizontal MuMTV transmission in BALB/c that is not observed in germinal transmission is integration of new MuMTV sequences in mammary cell DNA. Integration is mammary cell specific and constant at 2 to 3 copies/cell from tumor to tumor. (c) MuMTV expression is changed in mammary epithelial cells during hormonal carcinogenesis. The nature of the change is qualitatively similar in both BALB/c and BALB/cfC3H. Expression of envelope glycopeptides (glycoprotein with a molecular weight of 52,000) is induced, which correlates with amplification of MuMTV RNA sequence content. Quantitative differences exist in induced levels in BALB/c and BALB/cfC3H. (d) MuMTV RNA and a glycoprotein with a molecular weight of 52,000 were not inducible with dexamethasone in normal mammary epithelial cells in culture. These structural components were induced in both premalignant (BALB/cfC3H) and malignant (BALB/c and BALB/cfC3H) cells. MuMTV RNA was induced by dexamethasone in normal cells pretreated with 5-iodo-2'-deoxyuridine. (e) Both premalignant and malignant cells have altered (vis-à-vis normal) surfaces, discernible by differences in reactivity with concanavalin A in hemadsorption assays. Indirect evidence suggests that the alteration includes membrane incorporation of MuMTV-related determinants of a glycoprotein with a molecular weight of 52,000. (f) Malignant cells exhibit enhanced sensitivity to insulin for reinitiation of DNA synthesis and mitosis in contact-inhibited homotypical monolayers. These findings have been organized into a hormonal cocarcinogenesis hypothesis in which expression of germinally transmitted MuMTV genes is the proximal cause of neoplastic transformation.