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Submitted on September 15, 2006
Accepted on March 5, 2007
Institute of Biomedicine, Department of Anatomy, and Medicity Research Laboratory, University of Turku, Tykistökatu 6 A, 20520 Turku, Finland.; Department of Laboratory Medicine, Lund University, MAS University Hospital, CRC Ent 72, 20502 Malmö, Sweden; Turku Graduate School of Biomedical Sciences, Turku, Finland
* To whom correspondence should be addressed. E-mail: anu.kallio{at}utu.fi.
Tamoxifen (Tam) is widely used in chemotherapy of breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor (ER)-dependent modulation of gene expression. In addition, recent reports have shown that Tam also has nongenomic effects. We have previously reported induction of a rapid mitochondrial death program in breast cancer cells at pharmacological concentrations of Tam. Here we studied the upstream signaling events leading to mitochondrial disruption by Tam. We observed that 5 µM Tam rapidly induced sustained activation of extracellular signal-regulated kinase (ERK1/2) in ER-positive breast cancer cell lines (MCF-7 and T47D) and that PD98059 (inhibitor of ERK activation) was able to protect MCF-7 cells against Tam-induced death. This data suggests that activation of ERK has a primary role in the acute death response of the cells. In addition, inhibition of epidermal growth factor receptor (EGFR) opposed both Tam-induced ERK1/2 -phosphorylation and cell death which suggests that EGFR-associated mechanisms are involved in Tam-induced death. ERK1/2 phosphorylation was associated with a prolonged nuclear localization of ERK1/2 as determined by fluorescence microscopy with ERK2-GFP construct. 17
-estradiol (E2) was shown to exert a different kind of temporal pattern of ERK nuclear localization in comparison with Tam. Moreover, E2 was found to oppose the rapid effects of Tam in MCF-7 and T47D cells, but not in MDA-MB-231 cells, which implies a role for estrogen receptors in the protective effect of estrogen. The pure antiestrogen ICI182780 could not, however, prevent Tam-induced ERK1/2 phosphorylation, suggesting that the Tam-induced rapid cell death is primarily ER-independent or mediated by ICI182780 insensitive nongenomic mechanisms.
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