Effect of nuclear export inhibition on estrogen receptor regulation in breast cancer cells.
We used the Crm1 inhibitor leptomycin B (LMB) to examine a possible involvement of nuclear export in estrogen receptor alpha (ER) level and function in MCF-7 breast carcinoma cells. As revealed by immunofluorescence microscopy and western blotting with anti-ER antibodies, LMB produced an accumulation of ER in cell nuclei. LMB also partly abrogated ER elimination resulting from Hsp90 disruption and 17beta-estradiol (E(2))-induced ER downregulation. By contrast, it was ineffective on ER downregulation caused by the pure anti-estrogen fulvestrant. Finally, LMB inhibited E(2)-induced progesterone receptor expression and the expression of an estrogen response element-driven luciferase reporter gene in unstimulated and E(2)-stimulated cells. Altogether, the data reported here suggest that: i) ER undergoes nuclear export directly or indirectly involving exportin Crm1; ii) degradation of unliganded and of agonist-bound ER probably occurs in an extranuclear compartment, while it is not the case for ER bound to a pure anti-estrogen; and iii) optimal ER-mediated gene transactivation seems to require nucleocytoplasmic shuttle of the receptor.
Nonclercq
Denis
D
Laboratory of Histology and Experimental Cytology, Faculty of Medicine and Pharmacy, Université de Mons-Hainaut, Pentagone, Mons, Belgium.
Journé
Fabrice
F
Laïos
Ioanna
I
Chaboteaux
Carole
C
Toillon
Robert-Alain
RA
Leclercq
Guy
G
Laurent
Guy
G
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D011960:Receptors, Estrogen / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D005231:Fatty Acids, Unsaturated; D018942:Macrolides; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D000077267:Fulvestrant; D004958:Estradiol; C035359:monorden; C038753:leptomycin B