Endocrine Abstracts

Women worldwide are using progestins in combination with an estrogen to relieve menopausal symptoms. Although the progestin component of menopausal hormone therapies is effective in terms of preventing estrogen-induced endometrial cancer, it has been associated with an increased risk of developing invasive breast cancer. Notably, most studies investigating an association between progestins and breast cancer, have examined older progestins such as medroxyprogesterone acetate, norethisterone and levonorgestrel. Considering that a variety of progestins with distinct structures and functions are available, it is possible that not all progestins increase breast cancer risk. Our study directly compared the effects of selected progestins on the mRNA expression of genes that are markers for specific tumour cell behaviours such as proliferation and apoptosis, and showed that progestins differentially regulate the expression of these genes. Moreover, we investigated the role of signal transduction pathways in progestin-induced regulation of the above-mentioned processes. Specifically, we examined pathways known to play a crucial role in growth, survival and metastasis, such ERK1/2 and JNK. All progestins, except the newer progestin drospirenone (DRSP), increased proliferation and migration of the human T47D breast cancer cell line to the same extent. DRSP was also the only progestin that did not stimulate phosphorylation of the ERK1/2 and JNK pathways in the T47D cells. Moreover, blocking activation of these kinase pathways by highly selective inhibitors prevented the effects all the progestins, except DRSP, on proliferation, apoptosis and migration. These results suggest that activation of the ERK1/2 and JNK pathways may be a mechanism by which the older progestins increase breast cancer risk. Finally, the results also suggest that DRSP may promote breast cancer pathogenesis to a lesser extent that the older progestins used in this study.