On the Mechanism of Carcinogenesis by Mouse Mammary Tumor Virus

Abstract

Mouse mammary tumor virus (MMTV) is a classic example of a latently oncogenic retrovirus, its life cycle and tumorigenicity showing many parallels with the leukemia viruses of domestic cats, chickens and laboratory mice (1). Although indisputably linked to the development of particular cancers, such viruses do not themselves encode the oncogenes responsible for cell transformation. Epidemiologically, they are therefore very different from the various isolates of acutely oncogenic retroviruses, in which cellular proto-oncogene sequences have become transduced within the viral genomes (2). While the latter transform cells rapidly and efficiently, both in vitroand in vivo, the latently oncogenic viruses have little or no influence on cultured cells, and in the animal there is characteristically a long delay between exposure of the virus and overt manifestations of neo-plasia. With MMTV, mice are naturally infected by milk-borne virus at birth, yet tumors rarely arise before about 4 months of age, the norm being closer to 6 to 9 months (3,4; and chapter by Slagle and Butel). Most female mice are detectably viremic at pregnancy, and shed high levels of virus in the milk, but although a high proportion of the mammary epithelial cells can become productively infected, they remain apparently normal. Indeed, only very rare infected cells undergo transformation and expand clonally to dominate the resultant tumors, suggesting some stochastic process as opposed to a direct influence of a viral gene product