PMID- 25454348
OWN - NLM
STAT- MEDLINE
DCOM- 20150916
LR  - 20210109
IS  - 1878-0261 (Electronic)
IS  - 1574-7891 (Print)
IS  - 1574-7891 (Linking)
VI  - 9
IP  - 2
DP  - 2015 Feb
TI  - Oncogenic signaling in amphiregulin and EGFR-expressing PTEN-null human breast 
      cancer.
PG  - 527-43
LID - S1574-7891(14)00245-2 [pii]
LID - 10.1016/j.molonc.2014.10.006 [doi]
AB  - A subset of triple negative breast cancer (TNBC) is characterized by 
      overexpression of the epidermal growth factor receptor (EGFR) and loss of PTEN, 
      and patients with these determinants have a poor prognosis. We used cell line 
      models of EGFR-positive/PTEN null TNBC to elucidate the signaling networks that 
      drive the malignant features of these cells and cause resistance to EGFR 
      inhibitors. In these cells, amphiregulin (AREG)-mediated activation of EGFR 
      results in up-regulation of fibronectin (FN1), which is known to be a mediator of 
      invasive capacity via interaction with integrin beta1. EGFR activity in this PTEN 
      null background also results in Wnt/beta-catenin signaling and activation of 
      NF-kappaB. In addition, AKT is constitutively phosphorylated in these cells and is 
      resistant to gefitinib. Expression profiling demonstrated that AREG-activated 
      EGFR regulates gene expression differently than EGF-activated EGFR, and 
      functional analysis via genome-scale shRNA screening identified a set of genes, 
      including PLK1 and BIRC5, that are essential for survival of SUM-149 cells, but 
      are uncoupled from EGFR signaling. Thus, our results demonstrate that in cells 
      with constitutive EGFR activation and PTEN loss, critical survival genes are 
      uncoupled from regulation by EGFR, which likely mediates resistance to EGFR 
      inhibitors.
CI  - Copyright (c) 2014 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Kappler, Christiana S
AU  - Kappler CS
AD  - Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical 
      University of South Carolina, Charleston, SC 29425, USA. Electronic address: 
      kapplerc@musc.edu.
FAU - Guest, Stephen T
AU  - Guest ST
AD  - Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical 
      University of South Carolina, Charleston, SC 29425, USA.
FAU - Irish, Jonathan C
AU  - Irish JC
AD  - Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical 
      University of South Carolina, Charleston, SC 29425, USA.
FAU - Garrett-Mayer, Elizabeth
AU  - Garrett-Mayer E
AD  - Department of Public Health Science, Medical University of South Carolina, 
      Charleston, SC 29425, USA.
FAU - Kratche, Zachary
AU  - Kratche Z
AD  - Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical 
      University of South Carolina, Charleston, SC 29425, USA.
FAU - Wilson, Robert C
AU  - Wilson RC
AD  - Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical 
      University of South Carolina, Charleston, SC 29425, USA.
FAU - Ethier, Stephen P
AU  - Ethier SP
AD  - Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical 
      University of South Carolina, Charleston, SC 29425, USA.
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - CA16672/CA/NCI NIH HHS/United States
GR  - R01CA130933/CA/NCI NIH HHS/United States
GR  - P30 CA138313/CA/NCI NIH HHS/United States
GR  - R01 CA130933/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20141023
PL  - United States
TA  - Mol Oncol
JT  - Molecular oncology
JID - 101308230
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (EGF Family of Proteins)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Amphiregulin
MH  - Breast Neoplasms/genetics/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - EGF Family of Proteins/genetics/*metabolism
MH  - ErbB Receptors/genetics/*metabolism
MH  - Female
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - *PTEN Phosphohydrolase
MH  - *Wnt Signaling Pathway
PMC - PMC4304881
MID - NIHMS639911
OTO - NOTNLM
OT  - Epidermal growth factor receptor
OT  - PTEN
OT  - Triple-negative breast cancer
OT  - shRNA screen
EDAT- 2014/12/03 06:00
MHDA- 2015/09/17 06:00
PMCR- 2015/02/01
CRDT- 2014/12/03 06:00
PHST- 2014/09/23 00:00 [received]
PHST- 2014/10/15 00:00 [revised]
PHST- 2014/10/17 00:00 [accepted]
PHST- 2014/12/03 06:00 [entrez]
PHST- 2014/12/03 06:00 [pubmed]
PHST- 2015/09/17 06:00 [medline]
PHST- 2015/02/01 00:00 [pmc-release]
AID - S1574-7891(14)00245-2 [pii]
AID - MOL2201592527 [pii]
AID - 10.1016/j.molonc.2014.10.006 [doi]
PST - ppublish
SO  - Mol Oncol. 2015 Feb;9(2):527-43. doi: 10.1016/j.molonc.2014.10.006. Epub 2014 Oct 
      23.