signature=9293cc4bd6f47e4f2a5f299011c6e89e,cancer cells microarray paper for examRW

Molecular Profiling of Breast Cancer Cell Lines Defines Relevant Tumor Models and Provides a Resource for Cancer Gene Discovery

Jessica Kao1.,Keyan Salari1,2.,Melanie Bocanegra1,Yoon-La Choi1,3,Luc Girard4,Jeet Gandhi4,Kevin A. Kwei1,Tina Hernandez-Boussard2,Pei Wang5,Adi F.Gazdar4,John D.Minna4,Jonathan R.Pollack1* 1Department of Pathology,Stanford University,Stanford,California,United States of America,2Department of Genetics,Stanford University,Stanford,California,United States of America,3Department of Pathology,Samsung Medical Center,Sungkyunkwan University School of Medicine,Seoul,South Korea,4Hamon Center for Therapeutic Oncology Research,University of Texas Southwestern Medical Center,Dallas,Texas,United States of America,5Division of Public Health Sciences,Fred Hutchinson Cancer Research Center,Seattle,Washington,United States of America

Abstract

Background:Breast cancer cell lines have been used widely to investigate breast cancer pathobiology and new therapies.

Breast cancer is a molecularly heterogeneous disease,and it is important to understand how well and which cell lines best model that diversity.In particular,microarray studies have identified molecular subtypes–luminal A,luminal B,ERBB2-associated,basal-like and normal-like–with characteristic gene-expression patterns and underlying DNA copy number alterations(CNAs).Here,we studied a collection of breast cancer cell lines to catalog molecular profiles and to assess their relation to breast cancer subtypes.

Methods:Whole-genome DNA microarrays were used to profile gene expression and CNAs in a collection of52widely-used breast cancer cell lines,and comparisons were made to existing profiles of primary breast tumors.Hierarchical clustering was used to identify gene-expression subtypes,and Gene Set Enrichment Analysis(GSEA)to discover biological features of those subtypes.Genomic and transcriptional profiles were integrated to discover within high-amplitude CNAs candidate cancer genes with coordinately altered gene copy number and expression.

Findings:Transcriptional profiling of breast cancer cell lines identified one luminal and two basal-like(A and B)subtypes.

Luminal lines displayed an estrogen receptor(ER)signature and resembled luminal-A/B tumors,basal-A lines were associated with ETS-pathway and BRCA1signatures and resembled basal-like tumors,and basal-B lines displayed mesenchymal and stem/progenitor-cell http://www.doczj.com/doc/b0110b106c175f0e7cd13798.htmlpared to tumors,cell lines exhibited similar patterns of CNA,but an overall higher complexity of CNA(genetically simple luminal-A tumors were not represented),and only partial conservation of subtype-specific CNAs.We identified80high-level DNA amplifications and13multi-copy deletions,and the resident genes with concomitantly altered gene-expression,highlighting known and novel candidate breast cancer genes.

Conclusions:Overall,breast cancer cell lines were genetically more complex than tumors,but retained expression patterns with relevance to the luminal-basal subtype distinction.The compendium of molecular profiles defines cell lines suitable for investigations of subtype-specific pathobiology,cancer stem cell biology,biomarkers and therapies,and provides a resource for discovery of new breast cancer genes.

Citation:Kao J,Salari K,Bocanegra M,Choi Y-L,Girard L,et al.(2009)Molecular Profiling of Breast Cancer Cell Lines Defines Relevant Tumor Models and Provides

a Resource for Cancer Gene Discovery.PLoS ONE4(7):e6146.doi:10.1371/journal.pone.0006146

Editor:Mikhail V.Blagosklonny,Roswell Park Cancer Institute,United States of America

Received March19,2009;Accepted June2,2009;Published July3,2009

Copyright:?2009Kao et al.This is an open-access article distributed under the terms of the Creative Commons Attribution License,which permits unrestricted use,distribution,and reproduction in any medium,provided the original author and source are credited.

Funding:This work was supported by grants from the NIH(CA97139;J.R.P.),the California Breast Cancer Research Program,(8KB-0135;J.R.P.),and the Longenbaugh Foundation(J.D.M.).K.S.is a Paul&Daisy Soros Fellow and fellow of the Medical Scientist Training Program.The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.

Competing Interests:The authors have declared that no competing interests exist.

*E-mail:pollack1@http://www.doczj.com/doc/b0110b106c175f0e7cd13798.html

.These authors contributed equally to this work.

Introduction

Breast cancer,a leading cause of cancer death in women,is recognized to be a molecularly heterogeneous disease.Markers such as estrogen receptor(ER),progesterone receptor(PR)and ERBB2/HER2are used for prognostication,and to stratify patients for appropriately targeted therapies[1].

More recently,DNA microarray studies have suggested a refined classification of breast cancer,distinguishing five major subtypes based on different patterns of gene expression,underlying DNA copy number alterations(CNAs),and associated clinical outcomes[2–5].Luminal subtypes A and B are ER positive and share expression markers with the luminal epithelial layer of cells lining normal breast ducts.Luminal-A tumors are genetically