DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer

Oncotarget
Otília MenyhartBalázs Győrffy

Abstract

The majority of patients develop resistance against suppression of HER2-signaling mediated by trastuzumab in HER2 positive breast cancer (BC). HER2 overexpression activates multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade. MAPK phosphatases (MKPs) are essential regulators of MAPKs and participate in many facets of cellular regulation, including proliferation and apoptosis. We aimed to identify whether differential MKPs are associated with resistance to targeted therapy in patients previously treated with trastuzumab. Using gene chip data of 88 HER2-positive, trastuzumab treated BC patients, candidate MKPs were identified by Receiver Operator Characteristics analysis performed in R. Genes were ranked using their achieved area under the curve (AUC) values and were further restricted to markers significantly associated with worse survival. Functional significance of the two strongest predictive markers was evaluated in vitro by gene silencing in HER2 overexpressing, trastuzumab resistant BC cell lines SKTR and JIMT-1. The strongest predictive MKPs were DUSP4/MKP-2 (AUC=0.75, p=0.0096) and DUSP6/MKP-3 (AUC=0.77, p=5.29E-05). Higher expression for these correlated to worse survival (DUSP4: H...Continue Reading

References

Feb 13, 2001·Biochemical and Biophysical Research Communications·M T Yip-SchneiderM S Marshall
Mar 10, 2001·Nature·L Chang, M Karin
Apr 16, 2005·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Toru FurukawaAkira Horii
Oct 12, 2005·International Journal of Cancer. Journal International Du Cancer·Balazs GyörffyHermann Lage
May 15, 2007·Oncogene·A S DhillonW Kolch
Aug 25, 2007·Cancer Metastasis Reviews·Gen Sheng Wu
Mar 12, 2008·Cancer Metastasis Reviews·Stephen M Keyse
Apr 17, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Paul L NguyenJay R Harris
Jun 19, 2009·Nature Reviews. Cancer·José Baselga, Sandra M Swain
Nov 26, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Shaheenah DawoodSharon H Giordano
Apr 24, 2010·Cellular Oncology : the Official Journal of the International Society for Cellular Oncology·Maria Antonietta LucciEmma Villa-Moruzzi
Feb 4, 2011·Anti-cancer Agents in Medicinal Chemistry·Caroline Nunes-XavierRafael Pulido
Feb 24, 2011·Cancer Research·Joaquín ArribasJosep Lluís Parra-Palau
Jul 20, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Edith A PerezNorman Wolmark
Oct 14, 2011·The New England Journal of Medicine·Dennis SlamonUNKNOWN Breast Cancer International Research Group
Dec 17, 2011·BMC Bioinformatics·Qiyuan LiAron C Eklund
Jul 21, 2012·The FEBS Journal·Christopher J Caunt, Stephen M Keyse
Sep 12, 2012·International Journal of Cancer. Journal International Du Cancer·Benedikt GröschlWolfgang Dietmaier
Feb 26, 2013·Cancer Treatment Reviews·Susan DentSacha Howell
Apr 9, 2013·Cancer Treatment Reviews·Pradip DeBrian Leyland-Jones
Oct 10, 2013·The Journal of Pathology·Filippo Montemurro, Maurizio Scaltriti
Dec 12, 2013·Biomarkers in Medicine·Zsuzsanna MihályBalázs Győrffy
Jan 9, 2014·CA: a Cancer Journal for Clinicians·Rebecca SiegelAhmedin Jemal
Jan 8, 2015·The New England Journal of Medicine·Sara M TolaneyEric P Winer

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Citations

Sep 21, 2018·American Society of Clinical Oncology Educational Book·Mark D PegramStacy L Moulder
Mar 15, 2019·International Journal of Molecular Sciences·Caroline E Nunes-XavierRafael Pulido

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Datasets Mentioned

BETA
GSE22226
GSE22358
GSE42822

Methods Mentioned

BETA
transfection
gene knockdown

Software Mentioned

affy Bioconductor package
JetSet
ROC Bioconductor
R

Related Concepts

Related Feeds

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