Breast cancer is the most common cancer in women worldwide. Early pregnancy protects from breast cancer and it is a universal phenomenon. Rats and mice that undergo a full term pregnancy also have a greatly reduced susceptibility to chemical carcinogen induced mammary carcinogenesis compared to nulliparous rats and mice. We have demonstrated that short-term treatment with late pregnancy levels of estradiol with or without progesterone is effective in conferring protection against mammary carcinogenesis. Carcinogenesis is a multistep process which includes initiation, promotion and progression. In the present investigation we determined whether the hormone-induced protection is due to a block in the carcinogenic process at initiation and/or at promotion-progression steps. Virgin Lewis rats were implanted with silastic capsules containing estradiol and progesterone at 7 weeks of age. The silastic capsules were removed 2 weeks later. At 14 weeks of age, the rats were treated with 50 mg/kg of N-methyl-N-nitorosurea (MNU). The rats were divided into 2 groups, one group received continuous promotion with estradiol and progesterone for 9 months from week 14 and the other group of rats did not receive any promotion treatment. In another experiment rats were treated with MNU at 7 weeks of age and 2 weeks later were divided into 2 groups, one group received short-term protective hormone treatment for a duration of 3 weeks and the other group also received the protective hormone treatment but it also was given continuous promotion with estradiol and progesterone for 9 months to promote initiated cells. The controls in both the experiments received only the carcinogen treatment. During the course of the experiment mammary tumors were harvested and at the end of the experiment rats were terminated and mammary gland whole mounts were taken for analysis of latent mammary cancers. Proliferative index of latent mammary cancers was measured by cyclin D1 expression. Short-term protective hormone treatment given before or after the carcinogen induced protection against mammary carcinogenesis. Long-term promotion with hormones reversed the protective effect of the short-term protective hormone treatments. But the incidence of latent mammary cancers were similar in all the groups. Cyclin D1 expression levels were highest in the latent mammary cancers from the control group and lowest in the short-term hormone protected groups. The levels of cyclin D1 expression were intermediate in the long-term promotion groups. Short-term hormone induced protection against mammary carcinogenesis may be due to decreased promotional environment. Increasing the promotional environment increases the incidence of mammary cancers. Therefore, the data suggests that in hormone protected animals, initiation is not blocked while promotion/progression is blocked or decreased in the process of carcinogenesis.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]