Receptor Tyrosine Kinase Expression Predicts Response to Sunitinib in Breast Cancer

Philip M Spanheimer; Allison W Lorenzen; James P De Andrade; Mikhail V Kulak; Jennifer C Carr; George W Woodfield; Sonia L Sugg; Ronald J Weigel

doi:10.1245/s10434-015-4597-x

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Receptor Tyrosine Kinase Expression Predicts Response to Sunitinib in Breast Cancer

Journal article

Open access

Peer reviewed

Receptor Tyrosine Kinase Expression Predicts Response to Sunitinib in Breast Cancer

Philip M Spanheimer, Allison W Lorenzen, James P De Andrade, Mikhail V Kulak, Jennifer C Carr, George W Woodfield, Sonia L Sugg and Ronald J Weigel

Annals of surgical oncology, Vol.22(13), pp.4287-4294

12/2015

DOI: 10.1245/s10434-015-4597-x

PMCID: PMC5003404

PMID: 25971960

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http://doi.org/10.1245/s10434-015-4597-xView

Open Access

Abstract

Preliminary data indicate that tyrosine kinase inhibitors (TKIs) function through rearranged during transfection (RET) in breast cancer. However, TKIs are not specific and can block several receptor tyrosine kinases (RTKs). This study used cell lines and primary breast cancer specimens to determine factors associated with TKI response. Proliferation was assessed after short interfering RNA knockdown with or without sunitinib in breast cancer cell lines by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Breast cancer tissue and matched normal breast was obtained from 30 women with invasive breast carcinoma. Gene expression was assessed by reverse transcriptase-polymerase chain reaction. Fresh tissue was treated in vitro with sunitinib or control media for 30 min, and response was assessed by phosphorylation-specific western blot. The RTKs including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR1-3), platelet-derived growth factor receptor (PDGFRa/b), and Kit were overexpressed in triple-negative breast tumors relative to HER2- and estrogen receptor-alpha (ERα)-positive tumors and normal breast tissue. Knockdown of EGFR reduced in vitro proliferation in MCF-7 and MDA-MB-231 but not in SKBR-3 or ZR-75-1 breast cancer cells. With the exception of RET, response to sunitinib was independent of RTK expression in all four cell lines. Both ERα-positive and low-EGFR-expressing tumors had an increased in vitro sunitinib response, as determined by alteration of Erk activation. Expression of other RTKs and additional clinical factors were not associated with response. Triple-negative breast cancers overexpress RTKs but have decreased in vitro response to the TKI sunitinib. In addition to RET, TKIs that block EGFR may increase the therapeutic efficacy of TKIs in breast cancer.

Receptor, Epidermal Growth Factor - genetics

Prognosis

Apoptosis - drug effects

Humans

Middle Aged

RNA, Messenger - genetics

Drug Resistance, Neoplasm

Reverse Transcriptase Polymerase Chain Reaction

Breast Neoplasms - drug therapy

Blotting, Western

Breast Neoplasms - metabolism

Pyrroles - pharmacology

Receptor, Epidermal Growth Factor - metabolism

Signal Transduction - drug effects

Breast Neoplasms - pathology

Receptor, Epidermal Growth Factor - antagonists & inhibitors

Female

Indoles - pharmacology

Cell Proliferation - drug effects

Protein Kinase Inhibitors - pharmacology

Phosphorylation - drug effects

Tumor Cells, Cultured

Neoplasm Staging

Real-Time Polymerase Chain Reaction

Details

Title: Subtitle: Receptor Tyrosine Kinase Expression Predicts Response to Sunitinib in Breast Cancer
Creators: Philip M Spanheimer - Department of Surgery, University of Iowa, Iowa City, IA, USA
Allison W Lorenzen - Department of Surgery, University of Iowa, Iowa City, IA, USA
James P De Andrade - Department of Surgery, University of Iowa, Iowa City, IA, USA
Mikhail V Kulak - Department of Surgery, University of Iowa, Iowa City, IA, USA
Jennifer C Carr - Department of Surgery, University of Iowa, Iowa City, IA, USA
George W Woodfield - Department of Surgery, University of Iowa, Iowa City, IA, USA
Sonia L Sugg - Department of Surgery, University of Iowa, Iowa City, IA, USA
Ronald J Weigel - Department of Surgery, University of Iowa, Iowa City, IA, USA. ronald-Weigel@uiowa.edu
Resource Type: Journal article
Publication Details: Annals of surgical oncology, Vol.22(13), pp.4287-4294
DOI: 10.1245/s10434-015-4597-x
PMID: 25971960
PMCID: PMC5003404
NLM abbreviation: Ann Surg Oncol
ISSN: 1068-9265
eISSN: 1534-4681
Publisher: United States
Grant note: R01CA109294 / NCI NIH HHS R01CA183702 / NCI NIH HHS T32 CA148062 / NCI NIH HHS R01 CA109294 / NCI NIH HHS R01 CA183702 / NCI NIH HHS T32CA148062 / NCI NIH HHS
Language: English
Date published: 12/2015
Academic Unit: Molecular Physiology and Biophysics; Anatomy and Cell Biology; Surgery; Biochemistry and Molecular Biology
Record Identifier: 9984024535102771

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