Progestins inhibit the growth of MDA-MB-231 cells transfected with progesterone receptor complementary DNA

Because progesterone exerts its effects mainly via estrogen-dependent proge sterone receptor (PgR), the expression of progesterone's effects may be ove rshadowed by the priming effect of estrogen, PgR expression vectors were tr ansfected into estrogen receptor (ER)-alpha and PgR-negative breast cancer cells MDA-MB-231; thus the functions of progesterone could be studied indep endent of estrogens and ERs, Eight stable transfectant clones expressing bo th PgR isoform A and B were studied for their growth response to progestero ne and its analogues. Although progesterone had no effect on growth in the control transfectant, the hormone markedly inhibited DNA synthesis and cell growth in all of the PgR-transfectants dose-dependently from 10(112)-10(-6 ) M. This growth inhibition was associated with an arrest of cells in the G 0/G1 phase of the cell cycle. Progestins medroxyprogesterone acetate, Org20 58, and R5020 also strongly inhibited DNA synthesis, and their doses requir ed for maximal inhibition of 60-70% were 10(-17) M, 10(-13) M, and 10(-7) M , respectively. Antiprogestin ZK98299 alone had no effect, but the compound was capable of counteracting the inhibitory effect of progesterone. In con trast, RU486 inhibited DNA synthesis, and it showed no further effects when it was used concurrently with progesterone. These results indicate that pr ogestins are per se antiproliferative via a PgR-mediated mechanism in breas t cancer cells. More importantly, we have shown that progestins may exert e ffective inhibitory control over the cell growth if the PgR expression is r eactivated in ER- and PgR-negative breast cancer cells.