Our recent studies have shown that overexpression of aromatase results in increased tissue estrogenic activity and induction of hyperplastic and dysplastic lesions in female aromatase transgenic mammary glands. Our studies also show aromatase overexpression results in an increase in the expression of both estrogen and progesterone receptors, and their expression are maintained in the transgenic mammary tissue even without circulating ovarian estrogens. We have also demonstrated the increase in the expression of several growth factors and cell cycle genes in the aromatase transgenic mammary glands, which is consistent with the observed increase in PCNA levels and cellular proliferation. The present study examines how these markers as well as phenotypic changes are affected in the absence of ER alpha and PR and the use of aromatase transgenic mouse model for the prevention of breast cancer. The aromatic fatty acid phenylacetate (PA) and its analogs have come under intense investigation due to their ability to cause the growth arrest of a variety of neoplasia, including human breast cancer. We have previously determined that PA and its halide derivative 4-chlorophenylacetate (4-CPA) showed marked antitumor activity on estrogen-dependent breast cancer cells in vitro. To test the ability of 4-CPA to affect breast cancer carcinogenesis in vivo, we have utilized 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumor development in aromatase transgenic mice as a model system. Results showed that in the group of mice not receiving 4-CPA, approximately 50% of the animals developed palpable mammary tumors while the remaining 50% showed frank microscopic evidence of ductal carcinoma in-situ. In the 4-CPA-treated group, no palpable tumors were detected while on a microscopic level, only mild hyperplasia was evident in some animals. These results demonstrate the ability of 4-CPA to act as a potent low toxic, chemopreventative agent against the development of carcinogen-induced mammary cancer. Histological and biochemical changes induced by the 4-CPA in the mouse tissue will be discussed.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]