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Submitted on April 10, 2003
Accepted on July 26, 2004
INSERM U482, 184, rue du Faubourg Saint Antoine, 75012 Paris, France
* To whom correspondence should be addressed. E-mail: gaben{at}st-antoine.inserm.fr.
We have addressed the question of rapid, non-genomic mechanisms that may be involved in the mitogenic action of estrogens in hormone-dependent breast cancer cells. In quiescent, estrogen-deprived MCF-7 cells, estradiol did not induce a rapid activation of either the MAPK/ERK or PI-3K/Akt pathway whereas the entry into the cell cycle was documented by the successive inductions of cyclin D1 expression, Rb hyperphosphorylation, activity of the promoter of the cyclin A gene, and DNA synthesis. However, pharmacological inhibitors of the src family kinases (PP1) or of the PI-3K (LY294002) did prevent the entry of the cells into the cell cycle and inhibited the late G1 phase progression, whereas the inhibitor of MAPK/ERK activation (U0126) had only a partial inhibitory effect in the early G1 phase. In agreement with these results, siRNA targeting Akt strongly inhibited the estradiol-induced cell cycle progression monitored by the activation of the promoter of the cyclin A gene. The expression of siRNA targeting MAPK 1 and 2 also had a clear inhibitory effect on the estradiol-induced activation of the cyclin A promoter, and antagonized also the estradiol-induced transcription directed by the estrogen response element. Finally, transfection of the estrogen receptor into NIH 3T3 fibroblasts did not confer to the cells sensitivity to a mitogenic action of estradiol. We conclude that the induction of the cell cycle by estradiol does not require a direct activation of MAPK/ERK or PI-3K signaling protein kinase cascades, but that these kinases appear to have a permissive role in the cell cycle progression.
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