Medroxyprogesterone acetate accelerates the development and increases the incidence of mouse mammary tumors induced by dimethylbenzanthracene

Chemical induction of mammary tumors in mice requires usually a long latency period and is often complicated by high non-mammary tumor related mortality. Classically hormone stimulation has been used as the means to increase tumor incidence. The synthetic progestin medroxyproges-terone acetate (MPA) was postulated by some authors to increase mammary tumor incidence in various rodent models. However, controversy exists regarding the role of MPA in experimental and human carcinogenesis. In our study we tested the use of a protocol of combined MPA-and dimethylbenz[a]anthracene (DMBA) treatment for the obtention of mammary tumors with a short latency and with a lower toxicity than the classical multiple dose DMBA protocol. MPA was very effective in accelerating the development and increasing the incidence of mammary tumors induced by DMBA in CD2F1 mice. MPA by itself did not produce any mammary tumors. The mean latency for tumor development from the end of carcinogen treatment was 99± 51 days in the group that received a combination of MPA and four DMBA doses. This group showed significantly earlier mammary tumor incidence (P < 0.0001) and higher tumor numbers than the groups that received only DMBA. Mammary tumors were also analyzed for effects on the mutation rate affecting the Ha-ras and Ki-ras genes. Our data is consistent with MPA probably increasing the number of target cells at risk for mutation by the chemical carcinogen DMBA and possibly promoting the faster development of tumors.