Classical membrane progesterone receptors in murine mammary carcinomas: agonistic effects of progestins and RU-486 mediating rapid non-genomic effects.
In this article, we demonstrate the expression of functional progesterone binding sites at the cell membrane in murine mammary carcinomas that are stimulated by progestins and inhibited by antiprogestins. Using confocal immunofluorescence, ligand binding and cell compartment-specific western blots, we were able to identify the presence of the classical progesterone receptors. Medroxyprogesterone acetate (MPA) and RU-486 (1 × 10(-11) and 1 × 10(-8) M) behaved as agonists activating extracellular signal-regulated kinases (ERKs) and progestin-regulated proteins, except for Cyclin D1 and Tissue factor which failed to increase with 1 × 10(-8) M RU-486, an experimental condition that allows PR to bind DNA. These results predicted a full agonist effect at low concentrations of RU-486. Accordingly, at concentrations lower than 1 × 10(-11) M, RU-486 increased cell proliferation in vitro. This effect was abolished by incubation with the ERK kinase inhibitor PD 98059 or by OH-tamoxifen. In vivo, at a daily dose of 1.2 μg/kg body weight RU-486 increased tumor growth, whereas at 12 mg/kg induces tumor regression. Our results indicate that low concentrations of MPA and RU-486 induce similar agonistic non-genomic effects, whereas RU-486 at higher concentrations may inhibit cell proliferation by genomic-induced effects. This suggests that RU-486 should be therapeutically administered at doses high enough to guarantee its genomic inhibitory effect.
Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-CONICET, Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina.
María Cecilia
MC
Bottino
Juan Pablo
JP
Cerliani
Paola
P
Rojas
Sebastián
S
Giulianelli
Rocío
R
Soldati
Carolina
C
Mondillo
María Alicia
MA
Gorostiaga
Omar P
OP
Pignataro
Juan Carlos
JC
Calvo
J Silvio
JS
Gutkind
Panomwat Amornphimoltham
Alfredo A
AA
Molinolo
Isabel A
IA
Lüthy
Claudia
C
Lanari
D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000378:metabolism*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D015735:Mifepristone / Q000819:agonists* / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D011372:Progestins / Q000819:agonists* / Q000627:therapeutic use*; D011980:Receptors, Progesterone / Q000737:chemistry / Q000378:metabolism*; D013256:Steroids / Q000737:chemistry
D011372:Progestins; D011980:Receptors, Progesterone; D013256:Steroids; D015735:Mifepristone; D017258:Medroxyprogesterone Acetate