PMID- 18245484
OWN - NLM
STAT- MEDLINE
DCOM- 20080226
LR  - 20220331
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 3
DP  - 2008 Feb 1
TI  - Tamoxifen resistance in breast tumors is driven by growth factor receptor 
      signaling with repression of classic estrogen receptor genomic function.
PG  - 826-33
LID - 10.1158/0008-5472.CAN-07-2707 [doi]
AB  - Not all breast cancers respond to tamoxifen, and many develop resistance despite 
      initial benefit. We used an in vivo model of estrogen receptor (ER)-positive 
      breast cancer (MCF-7 xenografts) to investigate mechanisms of this resistance and 
      develop strategies to circumvent it. Epidermal growth factor receptor (EGFR) and 
      HER2, which were barely detected in control estrogen-treated tumors, increased 
      slightly with tamoxifen and were markedly increased when tumors became resistant. 
      Gefitinib, which inhibits EGFR/HER2, improved the antitumor effect of tamoxifen 
      and delayed acquired resistance, but had no effect on estrogen-stimulated growth. 
      Phosphorylated levels of p42/44 and p38 mitogen-activated protein kinases (both 
      downstream of EGFR/HER2) were increased in the tamoxifen-resistant tumors and 
      were suppressed by gefitinib. There was no apparent increase in phosphorylated 
      AKT (also downstream of EGFR/HER2) in resistant tumors, but it was nonetheless 
      suppressed by gefitinib. Phosphorylated insulin-like growth factor-IR (IGF-IR), 
      which can interact with both EGFR and membrane ER, was elevated in the 
      tamoxifen-resistant tumors compared with the sensitive group. However, 
      ER-regulated gene products, including total IGF-IR itself and progesterone 
      receptor, remained suppressed even at the time of acquired resistance. 
      Tamoxifen's antagonism of classic ER genomic function was retained in these 
      resistant tumors and even in tumors that overexpress HER2 (MCF-7 HER2/18) and are 
      de novo tamoxifen-resistant. In conclusion, EGFR/HER2 may mediate tamoxifen 
      resistance in ER-positive breast cancer despite continued suppression of ER 
      genomic function by tamoxifen. IGF-IR expression remains dependent on ER but is 
      activated in the tamoxifen-resistant tumors. This study provides a rationale to 
      combine HER inhibitors with tamoxifen in clinical studies, even in tumors that do 
      not initially overexpress EGFR/HER2.
FAU - Massarweh, Suleiman
AU  - Massarweh S
AD  - Department of Internal Medicine, Markey Cancer Center, University of Kentucky, 
      Lexington, Kentucky, USA.
FAU - Osborne, C Kent
AU  - Osborne CK
FAU - Creighton, Chad J
AU  - Creighton CJ
FAU - Qin, Lanfang
AU  - Qin L
FAU - Tsimelzon, Anna
AU  - Tsimelzon A
FAU - Huang, Shixia
AU  - Huang S
FAU - Weiss, Heidi
AU  - Weiss H
FAU - Rimawi, Mothaffar
AU  - Rimawi M
FAU - Schiff, Rachel
AU  - Schiff R
LA  - eng
GR  - P50 CA58183/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Quinazolines)
RN  - 0 (Receptors, Estrogen)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/*drug therapy/*enzymology/genetics
MH  - Drug Resistance, Neoplasm
MH  - Drug Synergism
MH  - Gefitinib
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Phosphorylation/drug effects
MH  - Quinazolines/pharmacology
MH  - Receptor, ErbB-2/antagonists & inhibitors/biosynthesis/genetics/*metabolism
MH  - Receptor, IGF Type 1/metabolism
MH  - Receptors, Estrogen/*antagonists & inhibitors/*genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Tamoxifen/*pharmacology
MH  - Transcription, Genetic
MH  - Xenograft Model Antitumor Assays
EDAT- 2008/02/05 09:00
MHDA- 2008/02/27 09:00
CRDT- 2008/02/05 09:00
PHST- 2008/02/05 09:00 [pubmed]
PHST- 2008/02/27 09:00 [medline]
PHST- 2008/02/05 09:00 [entrez]
AID - 68/3/826 [pii]
AID - 10.1158/0008-5472.CAN-07-2707 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Feb 1;68(3):826-33. doi: 10.1158/0008-5472.CAN-07-2707.