PMID- 26832794
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20220325
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 15
IP  - 3
DP  - 2016 Mar
TI  - EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for 
      Vandetanib.
PG  - 503-11
LID - 10.1158/1535-7163.MCT-15-0548-T [doi]
AB  - Expression of TFAP2C in luminal breast cancer is associated with reduced survival 
      and hormone resistance, partially explained through regulation of RET. TFAP2C 
      also regulates EGFR in HER2 breast cancer. We sought to elucidate the regulation 
      and functional role of EGFR in luminal breast cancer. We used gene knockdown (KD) 
      and treatment with a tyrosine kinase inhibitor (TKI) in cell lines and primary 
      cancer isolates to determine the role of RET and EGFR in regulation of p-ERK and 
      tumorigenesis. KD of TFAP2C decreased expression of EGFR in a panel of luminal 
      breast cancers, and chromatin immunoprecipitation sequencing (ChIP-seq) confirmed 
      that TFAP2C targets the EGFR gene. Stable KD of TFAP2C significantly decreased 
      cell proliferation and tumor growth, mediated in part through EGFR. While KD of 
      RET or EGFR reduced proliferation (31% and 34%, P < 0.01), combined KD reduced 
      proliferation greater than either alone (52% reduction, P < 0.01). The effect of 
      the TKI vandetanib on proliferation and tumor growth response of MCF-7 cells was 
      dependent upon expression of TFAP2C, and dual KD of RET and EGFR eliminated the 
      effects of vandetanib. The response of primary luminal breast cancers to TKIs 
      assessed by ERK activation established a correlation with expression of RET and 
      EGFR. We conclude that TFAP2C regulates EGFR in luminal breast cancer. Response 
      to vandetanib was mediated through the TFAP2C target genes EGFR and RET. 
      Vandetanib may provide a therapeutic effect in luminal breast cancer, and RET and 
      EGFR can serve as molecular markers for response.
CI  - (c)2016 American Association for Cancer Research.
FAU - De Andrade, James P
AU  - De Andrade JP
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa.
FAU - Park, Jung M
AU  - Park JM
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa.
FAU - Gu, Vivian W
AU  - Gu VW
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa.
FAU - Woodfield, George W
AU  - Woodfield GW
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa.
FAU - Kulak, Mikhail V
AU  - Kulak MV
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa.
FAU - Lorenzen, Allison W
AU  - Lorenzen AW
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa.
FAU - Wu, Vincent T
AU  - Wu VT
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa.
FAU - Van Dorin, Sarah E
AU  - Van Dorin SE
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa.
FAU - Spanheimer, Philip M
AU  - Spanheimer PM
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa.
FAU - Weigel, Ronald J
AU  - Weigel RJ
AD  - Department of Surgery, University of Iowa, Iowa City, Iowa. 
      Ronald-Weigel@uiowa.edu.
LA  - eng
GR  - P30 CA086862/CA/NCI NIH HHS/United States
GR  - R01 CA183702/CA/NCI NIH HHS/United States
GR  - T32 GM007337/GM/NIGMS NIH HHS/United States
GR  - T32CA148062/CA/NCI NIH HHS/United States
GR  - T32 CA148062/CA/NCI NIH HHS/United States
GR  - R01CA183702/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160201
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Piperidines)
RN  - 0 (Quinazolines)
RN  - 0 (TFAP2C protein, human)
RN  - 0 (Transcription Factor AP-2)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
RN  - YO460OQ37K (vandetanib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Biomarkers, Tumor
MH  - Breast Neoplasms/drug therapy/*genetics/*metabolism/pathology
MH  - Carcinogenesis/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Disease Models, Animal
MH  - ErbB Receptors/*genetics
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Humans
MH  - MCF-7 Cells
MH  - Piperidines/*pharmacology
MH  - Proto-Oncogene Proteins c-ret/genetics/metabolism
MH  - Quinazolines/*pharmacology
MH  - Transcription Factor AP-2/genetics/*metabolism
MH  - Tumor Burden/drug effects/genetics
MH  - Xenograft Model Antitumor Assays
PMC - PMC4783288
MID - NIHMS752163
COIS- CONFLICT OF INTEREST: The authors declare that they have no conflict of interest.
EDAT- 2016/02/03 06:00
MHDA- 2016/12/15 06:00
PMCR- 2017/03/01
CRDT- 2016/02/03 06:00
PHST- 2015/07/13 00:00 [received]
PHST- 2015/12/27 00:00 [accepted]
PHST- 2017/03/01 00:00 [pmc-release]
PHST- 2016/02/03 06:00 [entrez]
PHST- 2016/02/03 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
AID - 1535-7163.MCT-15-0548-T [pii]
AID - 10.1158/1535-7163.MCT-15-0548-T [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2016 Mar;15(3):503-11. doi: 10.1158/1535-7163.MCT-15-0548-T. 
      Epub 2016 Feb 1.