The relationship between affinity of progestins and antiprogestins for the progesterone receptor in breast cancer cells (ZR-PR-LT) and ability to down-regulate the receptor: evidence for heterospecific receptor modulation via the glucocorticoid receptor.

In a human breast cancer cell line (ZR-PR-LT) we have found a poor overall correlation between affinity of progestins and anti-progestins for the progesterone receptor (PGR), concentration required for receptor down-regulation and anti-proliferative potency. Medroxyprogesterone acetate (MPA) and the anti-progestin RU 38.486, which possess glucocorticoid and antiglucocorticoid activity, respectively, cause receptor down-regulation at lower concentrations than their Kdi for [3H] ORG 2058 binding sites. In addition dexamethasone markedly down-regulates PGR at concentrations which fail to interact with PGR suggesting that heterospecific modulation of PGR occurs via the glucocorticoid receptor. In contrast the progestin ORG2058 and the anti-progestin ZK 98.299 caused 50% PGR down-regulation at a concentration (EC50) 50-fold higher than their Kdi values. ZK 112.993 was 500-fold more potent at PGR down-regulation than ZK 98.299 but had only a 5-fold higher affinity for PGR. Anti-proliferative concentrations of progestins/anti-progestins showing were generally higher than either Kdi values or EC50 values.