Breast Cancer Research and Treatment

, Volume 126, Issue 3, pp 621–636

Classical membrane progesterone receptors in murine mammary carcinomas: agonistic effects of progestins and RU-486 mediating rapid non-genomic effects

  • María Cecilia Bottino
  • Juan Pablo Cerliani
  • Paola Rojas
  • Sebastián Giulianelli
  • Rocío Soldati
  • Carolina Mondillo
  • María Alicia Gorostiaga
  • Omar P. Pignataro
  • Juan Carlos Calvo
  • J. Silvio Gutkind
  • Panomwat Amornphimoltham
  • Alfredo A. Molinolo
  • Isabel A. Lüthy
  • Claudia Lanari
Preclinical study

DOI: 10.1007/s10549-010-0971-3

Cite this article as:
Bottino, M.C., Cerliani, J.P., Rojas, P. et al. Breast Cancer Res Treat (2011) 126: 621. doi:10.1007/s10549-010-0971-3
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Abstract

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.

Keywords

Membrane progesterone receptorsMammary carcinomasProgesterone receptor isoforms: membrane-initiated steroid signalingAntiprogestinsBreast cancer treatmentNon-genomic effectsProgestins

Abbreviations

chFCS

Steroid-stripped fetal calf serum

ERα

ER alpha

MISS

Membrane initiated steroid signaling

MPA

Medroxyprogesterone acetate

mPR

Membrane progesterone receptors

OH-Tam

OH-Tamoxifen

PD

PD 98059

Pg

Progesterone

PI

Propidium iodide

PR

Progesterone receptor

PR-A

PR isoform A

PR-B

PR isoform B

s.c

Subcutaneous

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • María Cecilia Bottino
    • 1
  • Juan Pablo Cerliani
    • 1
  • Paola Rojas
    • 1
  • Sebastián Giulianelli
    • 1
  • Rocío Soldati
    • 1
  • Carolina Mondillo
    • 1
  • María Alicia Gorostiaga
    • 1
  • Omar P. Pignataro
    • 3
  • Juan Carlos Calvo
    • 3
  • J. Silvio Gutkind
    • 4
  • Panomwat Amornphimoltham
    • 4
  • Alfredo A. Molinolo
    • 4
  • Isabel A. Lüthy
    • 2
  • Claudia Lanari
    • 1
  1. 1.Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas—CONICETBuenos AiresArgentina
  2. 2.Laboratorio de Hormonas y Cáncer, Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas—CONICETBuenos AiresArgentina
  3. 3.Departamento de Química Biológica, Facultad de Ciencias Exactas y NaturalesUniversidad de Buenos AiresBuenos AiresArgentina
  4. 4.Oral and Pharyngeal Cancer BranchNational Institute of Dental and Craniofacial Research National Institutes of HealthBethesdaUSA