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Downlo ent clinical trials show that combined oral dosing with estrogen and progestin increases the inciof breast cancer in postmenopausal women. Similarly, in a rat model system of mammary carciesis, the synthetic progestin medroxyprogesterone acetate (MPA) decreases latency and increases nce of 7,12-dimethylbenz(a)anthracene (DMBA)–induced mammary tumors. The goal of this was to compare the effects of four clinically relevant progestins, MPA, norgestrel (N-EL), norethe (N-ONE), and megestrol acetate (MGA), on DMBA-induced mammary carcinogenesis in the e experimental protocol involved implantation of 60-day release progestin pellets four weeks after ere treated with DMBA. In contrast to the effect of MPA, N-ONE, and N-EL, but not MGA, blocked -dependent carcinogenesis and a dose-dependent effect on tumor growth was shown for N-EL; did not alter tumor growth. Histopathologic studies showed extensive hyperplastic lesions in ary tissue of progestin-treated animals. Furthermore, following treatment with N-EL or N-ONE, nohistochemical staining for vascular endothelial growth factor in hyperplastic mammary tissue wer than in animals treated with DMBA plus MPA or DMBA alone. Expression of vascular enlial growth factor receptor-1, estrogen receptor α, and progesterone receptor was also lower in plastic mammary tissue in N-EL–, N-ONE–, and MGA-treated animals. Interestingly, N-EL stimuprogression of existing mammary tumors in DMBA/MPA-treated rats, suggesting stage-specific eff N-EL in this model. Because N-EL and N-ONE prevent tumor growth in the early stages of -induced mammary carcinogenesis in rats, these progestins may have potential as chemoprevenDMBA tive agents in women with no history of breast disease or family history of breast cancer. Cancer Prev Res;