The activity of the synthetic progestin medroxyprogesterone acetate on the invasive phenotype of ovarian cancer cells

Abstract

16003 Background: Androgens play an integral role in the physiologic and pathologic processes of the ovary. Yet it has been difficult to study the role of the androgen recptors (AR) separately from the other steroid receptors such as the progesterone receptor (PR) in ovarian cancer. This has been made more complicated because most synthetic progestins such as Medroxyprogesterone acetate (MPA) bind both PR and AR. The objectives of our study were: 1. To create an ovarian cancer cell line constitutively expressing only AR. 2. To compare the role of AR activated by the synthetic progestin MPA vs. the pure androgen dihydrotestosterone (DHT) on the invasiveness of human breast and ovarian cancer cells. 3. To investigate the role of matrix metalloproteases (MMP's) associated with invasion. Methods: ER- and PR- human breast (T47D-Y) and ovarian (OvCa 429) cancer cells were engineered to stably express AR. Immunocytochemistry and western blot analyses confirmed that these breast and ovarian cancer cell lines (called Y-AR and OvCa-AR respectively) are PR-, but AR+. Boyden chamber invasion assays were performed using Y-AR and OvCa-AR cells treated with either vehicle, MPA or DHT. The MMP's associated with invasion were further investigated using zymographic assays. Results: AR activation by either MPA or DHT increased the invasive potential of both breast (p<0.05) and ovarian cancer cells with MPA being significantly more effective than DHT at stimulating invasion. However, regardless of the ligand, activation of AR increases tumor cell invasion. To elucidate the MMP's associated with this activation in OvCa-AR cells, we used zymographic analysis. Interestingly, we found that MPA activation of AR decreases both the total level and activation of MMP-9 compared to DHT and vehicle control. Conclusions: Using our model system we are able to study the role of AR independent of PR on the biology of breast and ovarian cancer cells. Our studies suggest that the use of pharmacological doses of synthetic progestins may actually increase the invasive potential of ovarian cancer cells through AR. We hypothesize that blockade of downstream AR targets or the use of selective AR modulators (SARMS) may be of therapeutic value in the treatment of ovarian cancer. No significant financial relationships to disclose.