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Med1 plays a critical role in the development of tamoxifen resistance

Nagalingam, Arumugam; Tighiouart, Mourad; Rydén, Lisa LU ; Joseph, Leena; Landberg, Göran LU ; Saxena, Neeraj K. and Sharma, Dipali (2012) In Carcinogenesis 33(4). p.918-930
Abstract
Understanding the molecular pathways that contribute to the development of tamoxifen resistance is a critical research priority as acquired tamoxifen resistance is the principal cause of poor prognosis and death of patients with originally good prognosis hormone-responsive breast tumors. In this report, we provide evidence that Med1, an important subunit of mediator coactivator complex, is spontaneously upregulated during acquired tamoxifen-resistance development potentiating agonist activities of tamoxifen. Phosphorylated Med1 and estrogen receptor (ER) are abundant in tamoxifen-resistant breast cancer cells due to persistent activation of extracellular signal-regulated kinases. Mechanistically, phosphorylated Med1 exhibits nuclear... (More)
Understanding the molecular pathways that contribute to the development of tamoxifen resistance is a critical research priority as acquired tamoxifen resistance is the principal cause of poor prognosis and death of patients with originally good prognosis hormone-responsive breast tumors. In this report, we provide evidence that Med1, an important subunit of mediator coactivator complex, is spontaneously upregulated during acquired tamoxifen-resistance development potentiating agonist activities of tamoxifen. Phosphorylated Med1 and estrogen receptor (ER) are abundant in tamoxifen-resistant breast cancer cells due to persistent activation of extracellular signal-regulated kinases. Mechanistically, phosphorylated Med1 exhibits nuclear accumulation, increased interaction with ER and higher tamoxifen-induced recruitment to ER-responsive promoters, which is abrogated by inhibition of Med1 phosphorylation. Stable knockdown of Med1 in tamoxifen-resistant cells not only reverses tamoxifen resistance in vitro but also in vivo. Finally, higher expression levels of Med1 in the tumor significantly correlated with tamoxifen resistance in ER-positive breast cancer patients on adjuvant tamoxifen monotherapy. In silico analysis of breast cancer, utilizing published profiling studies showed that Med1 is overexpressed in aggressive subsets. These findings provide what we believe is the first evidence for a critical role for Med1 in tamoxifen resistance and identify this coactivator protein as an essential effector of the tamoxifen-induced breast cancer growth. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Carcinogenesis
volume
33
issue
4
pages
918 - 930
publisher
Oxford University Press
external identifiers
  • wos:000302493800024
  • scopus:84859592969
ISSN
0143-3334
DOI
10.1093/carcin/bgs105
language
English
LU publication?
yes
id
21232152-f59e-489e-8ed8-7ee11f8c5478 (old id 2587599)
date added to LUP
2012-06-01 09:38:30
date last changed
2017-09-24 03:03:19
@article{21232152-f59e-489e-8ed8-7ee11f8c5478,
  abstract     = {Understanding the molecular pathways that contribute to the development of tamoxifen resistance is a critical research priority as acquired tamoxifen resistance is the principal cause of poor prognosis and death of patients with originally good prognosis hormone-responsive breast tumors. In this report, we provide evidence that Med1, an important subunit of mediator coactivator complex, is spontaneously upregulated during acquired tamoxifen-resistance development potentiating agonist activities of tamoxifen. Phosphorylated Med1 and estrogen receptor (ER) are abundant in tamoxifen-resistant breast cancer cells due to persistent activation of extracellular signal-regulated kinases. Mechanistically, phosphorylated Med1 exhibits nuclear accumulation, increased interaction with ER and higher tamoxifen-induced recruitment to ER-responsive promoters, which is abrogated by inhibition of Med1 phosphorylation. Stable knockdown of Med1 in tamoxifen-resistant cells not only reverses tamoxifen resistance in vitro but also in vivo. Finally, higher expression levels of Med1 in the tumor significantly correlated with tamoxifen resistance in ER-positive breast cancer patients on adjuvant tamoxifen monotherapy. In silico analysis of breast cancer, utilizing published profiling studies showed that Med1 is overexpressed in aggressive subsets. These findings provide what we believe is the first evidence for a critical role for Med1 in tamoxifen resistance and identify this coactivator protein as an essential effector of the tamoxifen-induced breast cancer growth.},
  author       = {Nagalingam, Arumugam and Tighiouart, Mourad and Rydén, Lisa and Joseph, Leena and Landberg, Göran and Saxena, Neeraj K. and Sharma, Dipali},
  issn         = {0143-3334},
  language     = {eng},
  number       = {4},
  pages        = {918--930},
  publisher    = {Oxford University Press},
  series       = {Carcinogenesis},
  title        = {Med1 plays a critical role in the development of tamoxifen resistance},
  url          = {http://dx.doi.org/10.1093/carcin/bgs105},
  volume       = {33},
  year         = {2012},
}