Estradiol inhibits glucocorticoid receptor expression and induces glucocorticoid resistance in MCF-7 human breast cancer cells

Our study has shown that treatment of MCF-7 human breast cancer cells with 17-beta estradiol (E-2) produced significant decreases in glucocorticoid re ceptor (GR) concentrations and CR mRNA levels. E-2 pre-treatment of MCF-7 c ells stably transfected with the GR responsive pMTV-CAT reporter (MCF-7 MTV cells), caused significant attenuation of dexamethasone (DEX)-induced chlo ramphenicol acety] transferase (CAT). In MCF-7 cells transiently transfecte d with [(GRE)(3)-Luc] reporter plasmid. E-2 pre-treatment significantly sup pressed DEX-induced luciferase, which was abolished by the estrogen recepto r antagonist ICI 182,780. We examined the effect of chronic E-2 treatment a s well as E-2 withdrawal on GR Function and abundance. MCF-7-MTV cells were treated with vehicle (control) or E-2 for up to 16 days. A third group rec eived E-2 for 5 days followed by E-2 withdrawal from day 6 to 16. Chronic E -2 treatment almost totally abrogated DEX-induced CAT and reduced GR to ver y low levels. Interestingly, in the group subjected to E-2 withdrawal, neit her the DEX response nor GR abundance recovered and reached control values suggesting that the estrogen mediated suppression is long lasting and could not be easily reversed. The E-2 induced resistance to glucocorticoid actio n may be of potential clinical significance in a number of settings includi ng breast cancer, neuroendocrine response to stress and osteoporosis and co uld possibly contribute to the differences in glucocorticoid responsiveness among patients. (C) 2001 Elsevier Science Ltd. All rights reserved.