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Tamoxifen-induced Rapid Death of MCF-7 Breast Cancer Cells is mediated via ERK Signaling and can be abrogated by Estrogen.

Zheng, Aiping; Kallio, Anu and Härkönen, Pirkko LU (2007) In Endocrinology 148(6). p.2764-2777
Abstract
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 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 mu M Tam rapidly induced sustained activation of 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.... (More)
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 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 mu M Tam rapidly induced sustained activation of 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. These data suggest 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-green fluorescent protein construct. 17 beta-Estradiol was shown to exert a different kind of temporal pattern of ERK nuclear localization in comparison with Tam. Moreover, 17 beta-estradiol 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Endocrinology
volume
148
issue
6
pages
2764 - 2777
publisher
Endocrine Society
external identifiers
  • wos:000246572400025
  • scopus:34250805606
ISSN
0013-7227
DOI
10.1210/en.2006-1269
language
English
LU publication?
yes
id
48b6c91b-54a8-4b88-afb1-523060fb5120 (old id 166523)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17363451&dopt=Abstract
date added to LUP
2007-07-27 14:12:12
date last changed
2017-11-05 03:29:18
@article{48b6c91b-54a8-4b88-afb1-523060fb5120,
  abstract     = {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 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 mu M Tam rapidly induced sustained activation of 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. These data suggest 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-green fluorescent protein construct. 17 beta-Estradiol was shown to exert a different kind of temporal pattern of ERK nuclear localization in comparison with Tam. Moreover, 17 beta-estradiol 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.},
  author       = {Zheng, Aiping and Kallio, Anu and Härkönen, Pirkko},
  issn         = {0013-7227},
  language     = {eng},
  number       = {6},
  pages        = {2764--2777},
  publisher    = {Endocrine Society},
  series       = {Endocrinology},
  title        = {Tamoxifen-induced Rapid Death of MCF-7 Breast Cancer Cells is mediated via ERK Signaling and can be abrogated by Estrogen.},
  url          = {http://dx.doi.org/10.1210/en.2006-1269},
  volume       = {148},
  year         = {2007},
}