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Carcinoma Induction following Direct in Situ Transfer of v-Ha-ras into Rat Mammary Epithelial Cells Using Replication-defective Retrovirus Vectors¹

Department of Human Oncology [W. S. K., J. Y-B., M. J. L., M. N. G.] and Environmental Toxicology Center [B. W., M. N. G.], University of Wisconsin-Madison, Madison, Wisconsin 53792

Chemically induced mammary carcinomas often contain the activated Ha-ras oncogene. The role of this oncogene in the multistage process of carcinogenesis remains undefined. In order to model the role of ras in mammary carcinogenesis, gene transfer into adult rat mammary epithelial cells was accomplished by infusing helper-free, replication-defective retrovirus vectors into the central duct of each gland. In the initial experiments, the ß-galactosidase reporter gene was used to optimize the efficiency of this in situ gene transfer method. Stable infection of >0.1% of mammary cells could be achieved following exposure to the ß-galactosidase gene-expressing vector. v-Ha-ras was then introduced into in situ adult rat mammary epithelial cells using this method. Cellular infection frequencies of <1% resulted in the frequent and rapid appearance of mammary carcinomas without any further treatment. Tumors arising following v-Ha-ras oncogene transfer resembled those induced by chemical carcinogens in both the kinetics of their development and histopathological spectrum. These observations support the hypothesis that ras activation can act as an initiation event in chemically induced mammary carcinogenesis. However, only a small percentage of v-Ha-ras infected cells, even with hormonal promotion, were neoplastically transformed, suggesting that ras-driven transformation is not a one-step event.

¹ Supported by Grants CA44387 and CA28954 from the USPHS, NIH.

² To whom requests for reprints should be addressed, at K4/332, UWCCC, Department of Human Oncology, 600 Highland Avenue, Madison, WI 53792.

Received 11/21/90. Accepted 3/ 6/91.

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