Protoneoplasia: the molecular biology of murine mammary hyperplasia.

The mouse mammary tumor virus has provided a window into the inner workings of the mammary epithelial cell at the earliest stages of neoplasia. Techniques of molecular biology permitted us to look through that window revealing a new biology which deserves consideration as a model for mammary tumorigenesis in all species. According to this model the neoplastic process originates in a single mammary epithelial cell as a result of a critical genetic alteration, such as integration of MuMTV (MuMHV) into a key site in the mouse genome (Fig. 4). The genetic alteration immortalizes the cell and provides it with selective growth advantages which result in a clonal proliferation. This original proliferation emerges as the protoneoplastic mammary hyperplasia. The protoneoplastic cells have limited growth potential and are not obligated to undergo malignant transformation but they represent a genetically evolving population highly susceptible to full blown malignancy after exposure to carcinogens. Protoneoplastic cells which undergo further genetic alterations that provide additional selective growth advantages proliferate and emerge as malignant tumors. The genetic alterations are sometimes reflected by changes in viral DNA but this is not essential and most mouse mammary tumors probably do not occur as the result of new host-virus interactions. No doubt the current work on the mouse "int" loci will help define the genes responsible for the induction and maintenance of the protoneoplastic state. Since such host genes have proven so ubiquitous, one must also predict that analogous genes will be found in human mammary protoneoplasias. Detection of such sequences may help distinguish protoneoplastic processes from nonneoplastic, low risk hyperplasias in the human breast. Finally, the gene or genes involved in the more lethal malignant transformation await elucidation. Based on past and current progress one can be sure that the mouse mammary tumor system will help point the way.