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Carcinogenesis Advance Access originally published online on August 3, 2009
Carcinogenesis 2009 30(10):1696-1701; doi:10.1093/carcin/bgp187
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

CRK7 modifies the MAPK pathway and influences the response to endocrine therapy

Elizabeth Iorns1,{dagger},*, Sanne R. Martens-de Kemp2,{dagger}, Christopher J. Lord and Alan Ashworth

The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK
1 Present address: Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
2 Present address: Department of Otolaryngology/Head and Neck surgery, VU University Medical Center, Amsterdam 1007 MB, The Netherlands

* To whom correspondence should be addressed. Tel: +305 243 4612; Fax: +305 243 5885; Email: eiorns{at}med.miami.edu

Endocrine therapies, which inhibit estrogen receptor (ER){alpha} signaling, are the most common and effective treatment for ER{alpha}-positive breast cancer. However, the use of these agents is limited by the frequent development of resistance. The cyclin-dependent kinase family member CRK7 (aka CRKRS) was identified from an RNA interference screen for modifiers of tamoxifen sensitivity. Here, we demonstrate that silencing of CRK7 not only causes resistance to tamoxifen but also leads to resistance to additional endocrine therapies including ICI 182780 and estrogen deprivation, a model of aromatase inhibition. We show that CRK7 silencing activates the mitogen-activated protein kinase (MAPK)-signaling pathway, which causes a loss of ER dependence, resulting in endocrine therapy resistance. This study identifies a novel role for CRK7 in MAPK regulation and resistance to estrogen signaling inhibitors.

Abbreviations: ER, estrogen receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; 4OHT, 4-hydroxy-tamoxifen; RNAi, RNA interference; MAPK, mitogen-activated protein kinase; PCR, polymerase chain reaction; RB, retinoblastoma protein; RNAi, RNA interference; siRNA, small interfering RNA

{dagger} These authors contributed equally to this work.

Received December 1, 2008; revised July 25, 2009; accepted July 26, 2009.


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