PMID- 21292829
OWN - NLM
STAT- MEDLINE
DCOM- 20110601
LR  - 20220812
IS  - 1944-9917 (Electronic)
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 25
IP  - 3
DP  - 2011 Mar
TI  - The IGF pathway regulates ERalpha through a S6K1-dependent mechanism in breast cancer 
      cells.
PG  - 516-28
LID - 10.1210/me.2010-0373 [doi]
AB  - The IGF pathway stimulates malignant behavior of breast cancer cells. Herein we 
      identify the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) axis as a 
      critical component of IGF and estrogen receptor (ER)alpha cross talk. The insulin 
      receptor substrate (IRS) adaptor molecules function downstream of IGF-I receptor 
      and dictate a specific biological response, in which IRS-1 drives proliferation 
      and IRS-2 is linked to motility. Although rapamycin-induced mTOR inhibition has 
      been shown to block IGF-induced IRS degradation, we reveal differential effects 
      on motility (up-regulation) and proliferation (down-regulation). Because a 
      positive correlation between IRS-1 and ERalpha expression is thought to play a 
      central role in the IGF growth response, we investigated the potential role of 
      ERalpha as a downstream mTOR target. Small molecule inhibition and targeted knockdown 
      of S6K1 blocked the IGF-induced ERalpha(S167) phosphorylation and did not influence 
      ligand-dependent ERalpha(S118) phosphorylation. Inhibition of S6K1 kinase activity 
      consequently ablated IGF-stimulated S6K1/ERalpha association, estrogen response 
      element promoter binding and ERalpha target gene transcription. Moreover, 
      site-specific ERalpha(S167) mutation reduced ERalpha target gene transcription and 
      blocked IGF-induced colony formation. These findings support a novel link between 
      the IGF pathway and ERalpha, in which the translation factor S6K1 affects 
      transcription of ERalpha-regulated genes.
FAU - Becker, Marc A
AU  - Becker MA
AD  - Department of Pharmacology, Masonic Cancer Center, University of Minnesota, 
      Minneapolis, Minnesota 55455, USA.
FAU - Ibrahim, Yasir H
AU  - Ibrahim YH
FAU - Cui, Xiaojiang
AU  - Cui X
FAU - Lee, Adrian V
AU  - Lee AV
FAU - Yee, Douglas
AU  - Yee D
LA  - eng
GR  - R01 CA074285/CA/NCI NIH HHS/United States
GR  - R01CA74285/CA/NCI NIH HHS/United States
GR  - P30077598/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20110203
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (ESR1 protein, human)
RN  - 0 (Estrogen Receptor alpha)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1)
SB  - IM
MH  - Blotting, Western
MH  - Breast Neoplasms/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Chromatin Immunoprecipitation
MH  - Estrogen Receptor alpha/genetics/*metabolism
MH  - Humans
MH  - Immunoprecipitation
MH  - Insulin-Like Growth Factor I/*pharmacology
MH  - Phosphorylation/drug effects
MH  - Protein Binding/drug effects
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Ribosomal Protein S6 Kinases, 70-kDa/antagonists & 
      inhibitors/genetics/*metabolism
PMC - PMC3045742
EDAT- 2011/02/05 06:00
MHDA- 2011/06/02 06:00
PMCR- 2012/03/01
CRDT- 2011/02/05 06:00
PHST- 2011/02/05 06:00 [entrez]
PHST- 2011/02/05 06:00 [pubmed]
PHST- 2011/06/02 06:00 [medline]
PHST- 2012/03/01 00:00 [pmc-release]
AID - me.2010-0373 [pii]
AID - ME-10-0373 [pii]
AID - 10.1210/me.2010-0373 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2011 Mar;25(3):516-28. doi: 10.1210/me.2010-0373. Epub 2011 Feb 
      3.