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Receptor Tyrosine Kinase Expression Predicts Response to Sunitinib in Breast Cancer.

Abstract：

BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSION: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.

journal_name

Ann Surg Oncol

journal_title

Annals of surgical oncology

authors

Spanheimer PM,Lorenzen AW,De Andrade JP,Kulak MV,Carr JC,Woodfield GW,Sugg SL,Weigel RJ

doi

10.1245/s10434-015-4597-x

subject

Has Abstract

pub_date

2015-12-01 00:00:00

pages

4287-94

issue

eissn

1068-9265

issn

1534-4681

pii

10.1245/s10434-015-4597-x

journal_volume

pub_type

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Receptor Tyrosine Kinase Expression Predicts Response to Sunitinib in Breast Cancer.