Progestin inhibition of estrogen-dependent proliferation in ZR-75-1 human breast cancer cells: antagonism by insulin.
The effect of R5020 [17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione], a synthetic progestin, was studied in the hormone-responsive ZR-75-1 human breast cancer cell line. Following a 12-day incubation with increasing concentrations of R5020, the mitogenic effect of 17 beta-estradiol (E2, 1nM) was partially (60-80%) antagonized by the progestin, with a half-maximal effective concentration measured at about 30 pM. This effect of R5020 was completely reversed by the addition of physiological concentrations of bovine insulin, as well as by the potent antiprogestin RU486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl)-4, 9-estradien-3-one], but not by the antiandrogen hydroxyflutamide (alpha, alpha, alpha-trifluoro-2-methyl-4'-nitro-m-lactotoluidide). Moreover, the effect of R5020 required the presence of estrogens, thus further indicating a progesterone receptor (PgR)-mediated effect. Low (greater than 100 nM) concentrations of R5020 increased the specific binding of [125I]-insulin up to 2- to 2.5-fold in intact ZR-75-1 cells, an effect which was reversed by RU486. The effect was rapid, being nearly maximal after 24h of incubation with R5020. The PgR-mediated effect of R5020 on cell proliferation was abolished by the addition of a pure steroidal antiestrogen. The present results suggest a physiological role for progestins in increasing the responsiveness to insulin, which could, in turn, reverse the antiproliferative effect of progestins on estrogen action and thus decrease the efficacy of progestins in the treatment of breast cancer.
Poulin
R
R
Medical Research Council Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
Dufour
J M
JM
Labrie
F
F
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism*; D045167:Progesterone Congeners / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011397:Promegestone / Q000494:pharmacology; D011972:Receptor, Insulin / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013552:Swine; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D007328:Insulin; D045167:Progesterone Congeners; D011980:Receptors, Progesterone; D004958:Estradiol; D011397:Promegestone; D011972:Receptor, Insulin