Effect of nuclear export inhibition on estrogen receptor regulation in breast cancer cells

Abstract

We used the Crm1 inhibitor leptomycin B (LMB) to examine a possible involvement of nuclear export in estrogen receptor α (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 17β-estradiol (E2)-induced ER downregulation. By contrast, it was ineffective on ER downregulation caused by the pure anti-estrogen fulvestrant. Finally, LMB inhibited E2-induced progesterone receptor expression and the expression of an estrogen response element-driven luciferase reporter gene in unstimulated and E2-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. © 2007 Society for Endocrinology.