The introduction of activated oncogenes to mammary cells in vivo using retroviral vectors: a new model for the chemoprevention of premalignant and malignant lesions of the breast.

Breast cancer is an important disease site for chemopreventive intervention. The current in vivo rodent models for breast cancer do not adequately approximate the human disease. Thus, we developed a new series of models based on the direct introduction of activated oncogenes into in situ mammary ductal cells in the rat. So far we have introduced both activated ras and neu into the mammary parenchyma of the rat. Both oncogenes cause the development of mammary carcinomas without any additional exogenous intervention. The activated neu gene is, however, 200 times more penetrant than the activated ras gene. The carcinomas induced by both genes are more aggressive than those induced by chemical carcinogens. They are more often transplantable, locally invasive, and metastatic. Tumors arising from the introduction of the neu oncogene have a greater histopathological resemblance to human breast cancers than those associated with ras insertion. For example, within a week post-introduction of neu, lesions resembling ductal carcinomas in situ are observed in the rat mammary gland. These do not occur following ras introduction or exposure to chemical carcinogens. These models are helping to better define the cellular and molecular events associated with the multistage progression of breast cancer. They are also being used to develop models to evaluate chemopreventive approaches for breast cancer. For example, in the area of cancer prevention we have shown that hormonal intervention is more effective in preventing neu-initiated breast cancers than ras-initiated breast cancers. We have also shown that the chemopreventive monoterpene, d-limonene, can prevent ras-induced mammary tumors in this model.(ABSTRACT TRUNCATED AT 250 WORDS)