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.
Department of Therapeutics and Pharmacology, Queen's University of Belfast, U.K.
H W
HW
van den Berg
M
M
Lynch
J H
JH
Martin
D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006067:Gonanes / Q000494:pharmacology; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D011282:Pregnenediones / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism
D006067:Gonanes; D011282:Pregnenediones; D045167:Progesterone Congeners; D011372:Progestins; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; D015735:Mifepristone; D003907:Dexamethasone; D017258:Medroxyprogesterone Acetate; C053238:onapristone