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Incidence of c-Ki-ras Activation in N-Methyl-N-nitrosourea-induced Mammary Carcinomas in Pituitary-isografted Mice¹

Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720

We found previously that mouse mammary epithelial cells cultured in the presence of the mammogenic hormones progesterone and prolactin and treated with the carcinogen N-methyl-N-nitrosourea produced a high frequency of hyperplastic alveolar nodules and carcinomas with squamous metaplasia upon transplantation to syngeneic mice. The majority of these mammary transformants had an activated c-Ki-ras protooncogene with a specific point mutation in codon 12 (G35 to A35). To determine whether these in vitro findings parallel mammary carcinogenesis in vivo, virgin female mice were pituitary isografted to increase their circulating levels of progesterone and prolactin. The pituitary isograft results in an increase in proliferation, leading to lobulo-alveolar development and differentiation of the mammary epithelial cells. Five weeks after pituitary isografting, the mice were treated with a single injection of N-methyl-N-nitrosourea (50 µg/g body weight). Greater than 90% of the N-methyl-N-nitrosourea-treated mice developed mammary carcinomas between 3 and 7 months after treatment. The majority (75%) of the carcinomas had histopathology identical to that of tumors induced in vitro in the presence of progesterone and prolactin. A number of the mammary cancers (17%) induced in pituitary-isografted mice also had the identical point mutation in the c-Ki-ras proto-oncogene found in the in vitro studies. These results suggest that the hormonal milieu around the time of carcinogen exposure affects not only the incidence and phenotype of the mammary transformants but also the molecular events associated with mammary carcinogenesis.

¹ This research was supported by Grants CA-05388 and CA-09041 awarded by the NIH, Department of Health and Human Services, and Grant 1-523865-36647 from the University of California Cancer Research Coordinating Committee.

² To whom requests for reprints should be addressed, at Cancer Research Laboratory, Room 491, Life Sciences Addition, University of California, Berkeley, CA 94720.

³ Present address: Molecular Biology and Virology Laboratory, The Salk Institute, La Jolla, CA 92037.

Received 5/ 1/92. Accepted 8/ 8/92.

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