Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells

Medroxyprogesterone acetate (MPA), which is frequently used as second line hormonal therapy for the treatment of metastatic breast cancer, binds with high affinity to the progesterone receptor (PR). However, the androgenic si de-effects of MPA suggest that it may also activate androgen receptor (AR) regulated pathways. Treatment of the human breast cancer cell lines MDA-MB- 453, ZR-75-1 and T47-D with high dose (100 nM) MPA resulted in 26-30% inhib ition of cell growth, which was partially reversed by co-treatment with a 1 0-fold excess of the synthetic antiandrogen, anandron. Scatchard analysis d emonstrated specific, high affinity (non-PR) binding of [H-3]MPA to cytosol s prepared from the PR - /AR + MDA-MB-453 and PR + /AR + ZR-75-1, but not t he PR - /AR - BT-20 breast cancer cell lines. Competition of [H-3]MPA bindi ng to MDA-MB-453 cytosols by equimolar concentrations of androgens (5 alpha -dihydrotestosterone (DHT), R1881) and the antiandrogen, anandron was consi stent with binding of MPA to the AR. In ZR-75-1 cell cytosol fractions, DHT , R1881 and anandron only partially competed out [H-3]MPA binding, suggesti ng that androgens displace [H-3]MPA binding to AR but not to PR. Induction by MPA of AR transactivation was demonstrated in MDA-MB-453 and ZR-75-1 cel ls, and in the CV-1 cell line transfected with a full-length AR. In these c ell lines the increased activity of the androgen responsive reporter gene ( MMTV-CAT) by 1 nM MPA was fully (MDA-MB-453, CV-1) or partially (ZR-75-1) i nhibited by co-culture with I mu M anandron. These findings indicate that M PA is an AR agonist and suggest that the in vivo effects of MPA in breast c ancer patients may in part be mediated by the AR. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.