Transfection of activated Ha-ras protooncogenes causes mouse mammary hyperplasia

ras protooncogenes activated by a point mutation have been implicated in the initiation of mammary carcinogenesis. However, the nature of phenotypic alterations induced by activated ras protoonocogenes during initiation has not been well understood. In the present studies, the phenotypic manifestation of activated ras genes was directly analyzed by transfecting them into normal mouse mammary epithelial cells. The ras genes were cotransfected with pSV2neo which expresses the bacterial neomycin resistance gene to partially select for successful transfectants in culture. Transfection of activated Ha-ras protooncogenes, containing a point mutation in codon 12, caused hyperplasia in the mouse mammary gland following transplantation. Hyperplastic phenotype is a prerequisite for neoplastic development. The hyperplasias induced by the activated Ha-ras protooncogenes, however, were not immortal in vivo, another essential characteristic of preneoplastic and neoplastic mouse mammary cells. Control cells transfected only with pSV2neo did not produce any hyperplasia. These results suggest that a functional role of activated ras protooncogenes in the initiation of mouse mammary carcinogenesis may be the induction of a hyperplastic phenotype, a prelude to neoplastic development.