EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

James P De Andrade; Jung M Park; Vivian W Gu; George W Woodfield; Mikhail V Kulak; Allison W Lorenzen; Vincent T Wu; Sarah E Van Dorin; Philip M Spanheimer; Ronald J Weigel

doi:10.1158/1535-7163.MCT-15-0548-T

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EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

Journal article

Open access

Peer reviewed

EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

James P De Andrade, Jung M Park, Vivian W Gu, George W Woodfield, Mikhail V Kulak, Allison W Lorenzen, Vincent T Wu, Sarah E Van Dorin, Philip M Spanheimer and Ronald J Weigel

Molecular cancer therapeutics, Vol.15(3), pp.503-511

03/2016

DOI: 10.1158/1535-7163.MCT-15-0548-T

PMCID: PMC4783288

PMID: 26832794

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https://doi.org/10.1158/1535-7163.MCT-15-0548-TView

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Abstract

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.

Proto-Oncogene Proteins c-ret - metabolism

Humans

ErbB Receptors - genetics

Biomarkers, Tumor

Carcinogenesis - metabolism

Transcription Factor AP-2 - metabolism

Breast Neoplasms - metabolism

MCF-7 Cells

Piperidines - pharmacology

Female

Tumor Burden - genetics

Antineoplastic Agents - pharmacology

Gene Expression Regulation, Neoplastic - drug effects

Disease Models, Animal

Carcinogenesis - genetics

Breast Neoplasms - drug therapy

Xenograft Model Antitumor Assays

Transcription Factor AP-2 - genetics

Animals

Breast Neoplasms - genetics

Tumor Burden - drug effects

Breast Neoplasms - pathology

Cell Line, Tumor

Cell Proliferation - drug effects

Quinazolines - pharmacology

Proto-Oncogene Proteins c-ret - genetics

Details

Title: Subtitle: EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib
Creators: James P De Andrade - Department of Surgery, University of Iowa, Iowa City, Iowa
Jung M Park - Department of Surgery, University of Iowa, Iowa City, Iowa
Vivian W Gu - Department of Surgery, University of Iowa, Iowa City, Iowa
George W Woodfield - Department of Surgery, University of Iowa, Iowa City, Iowa
Mikhail V Kulak - Department of Surgery, University of Iowa, Iowa City, Iowa
Allison W Lorenzen - Department of Surgery, University of Iowa, Iowa City, Iowa
Vincent T Wu - Department of Surgery, University of Iowa, Iowa City, Iowa
Sarah E Van Dorin - Department of Surgery, University of Iowa, Iowa City, Iowa
Philip M Spanheimer - Department of Surgery, University of Iowa, Iowa City, Iowa
Ronald J Weigel - Department of Surgery, University of Iowa, Iowa City, Iowa. Ronald-Weigel@uiowa.edu
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.15(3), pp.503-511
DOI: 10.1158/1535-7163.MCT-15-0548-T
PMID: 26832794
PMCID: PMC4783288
NLM abbreviation: Mol Cancer Ther
ISSN: 1535-7163
eISSN: 1538-8514
Publisher: United States
Grant note: T32 CA148062 / NCI NIH HHS T32 GM007337 / NIGMS NIH HHS R01 CA183702 / NCI NIH HHS T32CA148062 / NCI NIH HHS R01CA183702 / NCI NIH HHS P30 CA030199 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 03/2016
Academic Unit: Molecular Physiology and Biophysics; Anatomy and Cell Biology; Surgery; Biochemistry and Molecular Biology
Record Identifier: 9984025257702771

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