Home LiteratureArticle Details
PMID: 19582160 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery.

PloS one ·Vol. 4 ·No. 7 ·2009-07-03 ·Pages e6146

Kao J, Salari K, Bocanegra M, Choi YL, Girard L, Gandhi J, Kwei KA, Hernandez-Boussard T, Wang P, Gazdar AF, Minna JD, Pollack JR

Abstract

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. Whole-genome DNA microarrays were used to profile gene expression and CNAs in a collection of 52 widely-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. 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 BRCA1 signatures and resembled basal-like tumors, and basal-B lines displayed mesenchymal and stem/progenitor-cell characteristics. Compared 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 identified 80 high-level DNA amplifications and 13 multi-copy deletions, and the resident genes with concomitantly altered gene-expression, highlighting known and novel candidate breast cancer genes. 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.

MeSH Terms
Base Sequence Blotting, Western Breast Neoplasms/genetics,pathology Cell Line, Tumor DNA Primers Female Gene Expression Profiling Genes, BRCA1 Humans Immunohistochemistry Oligonucleotide Array Sequence Analysis Polymerase Chain Reaction RNA, Messenger/genetics Transcription, Genetic
Chemicals
DNA Primers RNA, Messenger
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Kao Jessica
Department of Pathology, Stanford University, Stanford, CA, USA.
Salari Keyan
Bocanegra Melanie
Choi Yoon-La
Girard Luc
Gandhi Jeet
Kwei Kevin A
Hernandez-Boussard Tina
Wang Pei
Gazdar Adi F
Minna John D
Pollack Jonathan R
References (102)
102 references, click to expand
  1. Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells.
    Cancer Res. 1994 Dec 15;54(24):6348-52 PMID: 7987827
  2. ETS transcription factors: possible targets for cancer therapy.
    Cancer Sci. 2004 Aug;95(8):626-33 PMID: 15298723
  3. Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB.
    J Biol Chem. 2004 Feb 27;279(9):7576-83 PMID: 14662759
  4. A role for the scaffolding adapter GAB2 in breast cancer.
    Nat Med. 2006 Jan;12(1):114-21 PMID: 16369543
  5. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions.
    Cancer Res. 2005 Jun 1;65(11):4728-38 PMID: 15930291
  6. Origins of breast cancer subtypes and therapeutic implications.
    Nat Clin Pract Oncol. 2007 Sep;4(9):516-25 PMID: 17728710
  7. Interferon-alpha activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes.
    Gastroenterology. 2002 Apr;122(4):1020-34 PMID: 11910354
  8. Relevance of breast cancer cell lines as models for breast tumours: an update.
    Breast Cancer Res Treat. 2004 Feb;83(3):249-89 PMID: 14758095
  9. Autocrine transforming growth factor-beta signaling mediates Smad-independent motility in human cancer cells.
    J Biol Chem. 2003 Jan 31;278(5):3275-85 PMID: 12421823
  10. Breast cancer classification and prognosis based on gene expression profiles from a population-based study.
    Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10393-8 PMID: 12917485
  11. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer.
    Genes Chromosomes Cancer. 2006 Nov;45(11):1033-40 PMID: 16897746
  12. MUC1 oncoprotein stabilizes and activates estrogen receptor alpha.
    Mol Cell. 2006 Jan 20;21(2):295-305 PMID: 16427018
  13. Cohesin cleavage by separase required for anaphase and cytokinesis in human cells.
    Science. 2001 Aug 17;293(5533):1320-3 PMID: 11509732
  14. Repeated observation of breast tumor subtypes in independent gene expression data sets.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23 PMID: 12829800
  15. GIT1 functions in a motile, multi-molecular signaling complex that regulates protrusive activity and cell migration.
    J Cell Sci. 2002 Apr 1;115(Pt 7):1497-510 PMID: 11896197
  16. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma.
    Mod Pathol. 2006 Feb;19(2):264-71 PMID: 16341146
  17. Potentiation of estrogen receptor transcriptional activity by breast cancer amplified sequence 2.
    Biochem Biophys Res Commun. 2005 Mar 11;328(2):393-8 PMID: 15694360
  18. Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer.
    Cancer Res. 2004 May 1;64(9):3037-45 PMID: 15126339
  19. Breast cancer, stem/progenitor cells and the estrogen receptor.
    Trends Endocrinol Metab. 2004 Jul;15(5):193-7 PMID: 15223047
  20. Gene expression profiling predicts clinical outcome of breast cancer.
    Nature. 2002 Jan 31;415(6871):530-6 PMID: 11823860
  21. Mammary stem cells and breast cancer.
    Cell Mol Life Sci. 2007 Dec;64(24):3248-60 PMID: 17955177
  22. Expression profiling of epithelial plasticity in tumor progression.
    Oncogene. 2003 Oct 16;22(46):7155-69 PMID: 14562044
  23. Utilizing prognostic and predictive factors in breast cancer.
    Curr Treat Options Oncol. 2005 Mar;6(2):147-59 PMID: 15717996
  24. Prospective identification of tumorigenic breast cancer cells.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8 PMID: 12629218
  25. CD44 in cancer progression: adhesion, migration and growth regulation.
    J Mol Histol. 2004 Mar;35(3):211-31 PMID: 15339042
  26. Molecular characterization of human telomerase reverse transcriptase-immortalized human fibroblasts by gene expression profiling: activation of the epiregulin gene.
    Cancer Res. 2003 Apr 15;63(8):1743-7 PMID: 12702554
  27. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair.
    Nat Genet. 2008 Jan;40(1):102-7 PMID: 18066063
  28. Divergent gene regulation and growth effects by NF-kappa B in epithelial and mesenchymal cells of human skin.
    Oncogene. 2003 Apr 3;22(13):1955-64 PMID: 12673201
  29. TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling.
    Cancer Res. 2007 Sep 15;67(18):8439-43 PMID: 17875680
  30. The Ret receptor tyrosine kinase pathway functionally interacts with the ERalpha pathway in breast cancer.
    Cancer Res. 2008 May 15;68(10):3743-51 PMID: 18483257
  31. Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue.
    Breast Cancer Res Treat. 2001 May;67(2):93-109 PMID: 11519870
  32. Basal-like breast cancer and the BRCA1 phenotype.
    Oncogene. 2006 Sep 25;25(43):5846-53 PMID: 16998499
  33. Modelling breast cancer: one size does not fit all.
    Nat Rev Cancer. 2007 Sep;7(9):659-72 PMID: 17721431
  34. Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier.
    Cancer Res. 1998 Aug 1;58(15):3237-42 PMID: 9699648
  35. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation.
    J Cell Biol. 2003 Feb 3;160(3):341-53 PMID: 12551952
  36. Molecular portraits of human breast tumours.
    Nature. 2000 Aug 17;406(6797):747-52 PMID: 10963602
  37. Breast cancer: origins and evolution.
    J Clin Invest. 2007 Nov;117(11):3155-63 PMID: 17975657
  38. Gene expression profiling of breast cell lines identifies potential new basal markers.
    Oncogene. 2006 Apr 6;25(15):2273-84 PMID: 16288205
  39. Growth inhibition of breast cancer cells by Grb2 downregulation is correlated with inactivation of mitogen-activated protein kinase in EGFR, but not in ErbB2, cells.
    Oncogene. 1999 Feb 11;18(6):1325-32 PMID: 10022814
  40. RNA interference-based functional dissection of the 17q12 amplicon in breast cancer reveals contribution of coamplified genes.
    Genes Chromosomes Cancer. 2006 Aug;45(8):761-9 PMID: 16708353
  41. Comparison of features of human breast cancer cell lines and their corresponding tumors.
    Clin Cancer Res. 1998 Dec;4(12):2931-8 PMID: 9865903
  42. A comparison of gene expression signatures from breast tumors and breast tissue derived cell lines.
    Dis Markers. 2001;17(2):99-109 PMID: 11673656
  43. MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion.
    Oncogene. 2003 Mar 6;22(9):1324-32 PMID: 12618757
  44. Unlocking the potential of the human genome with RNA interference.
    Nature. 2004 Sep 16;431(7006):371-8 PMID: 15372045
  45. The valosin-containing protein (VCP) is a target of Akt signaling required for cell survival.
    J Biol Chem. 2006 May 19;281(20):14307-13 PMID: 16551632
  46. Characterization of cells and gene-targeted mice deficient for the p53-binding kinase homeodomain-interacting protein kinase 1 (HIPK1).
    Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5431-6 PMID: 12702766
  47. Regulation of the Erk2-Elk1 signaling pathway and megakaryocytic differentiation of Bcr-Abl(+) K562 leukemic cells by Gab2.
    Blood. 2002 Feb 15;99(4):1388-97 PMID: 11830491
  48. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma.
    Clin Cancer Res. 2004 Aug 15;10(16):5367-74 PMID: 15328174
  49. The Stanford Microarray Database: implementation of new analysis tools and open source release of software.
    Nucleic Acids Res. 2007 Jan;35(Database issue):D766-70 PMID: 17182626
  50. Transforming function of the LSM1 oncogene in human breast cancers with the 8p11-12 amplicon.
    Oncogene. 2007 Mar 29;26(14):2104-14 PMID: 17001308
  51. Rad51 overexpression promotes alternative double-strand break repair pathways and genome instability.
    Oncogene. 2004 Jan 15;23(2):546-53 PMID: 14724582
  52. Posttranscriptional regulation of the c-myb proto-oncogene in estrogen receptor-positive breast cancer cells.
    Clin Cancer Res. 1995 Feb;1(2):235-43 PMID: 9815978
  53. A role for the transcription factor HEY1 in glioblastoma.
    J Cell Mol Med. 2009 Jan;13(1):136-46 PMID: 18363832
  54. Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2.
    Oncogene. 2007 Apr 26;26(19):2809-14 PMID: 17086211
  55. Tumour-initiating cells vs. cancer 'stem' cells and CD133: what's in the name?
    Biochem Biophys Res Commun. 2007 Apr 20;355(4):855-9 PMID: 17307142
  56. Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand breaks by homologous recombination in vertebrate cells.
    Mol Cell Biol. 2003 Aug;23(15):5421-30 PMID: 12861027
  57. An oncogenic role for the phosphorylated h-subunit of human translation initiation factor eIF3.
    J Biol Chem. 2008 Aug 29;283(35):24047-60 PMID: 18544531
  58. The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells.
    Cancer Cell. 2005 Feb;7(2):155-65 PMID: 15710328
  59. Evaluation of oestrogen receptor expression in breast cancer by quantification of mRNA.
    Histopathology. 2007 Dec;51(6):829-36 PMID: 18042072
  60. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.
    Cancer Res. 2008 Aug 1;68(15):6084-91 PMID: 18676830
  61. Transcriptional profiling of human microvascular endothelial cells in the proliferative and quiescent state using cDNA arrays.
    Angiogenesis. 1999;3(3):211-9 PMID: 14517420
  62. Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines.
    Mol Cancer Res. 2007 Feb;5(2):195-201 PMID: 17314276
  63. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland.
    Cell. 2006 Dec 1;127(5):1041-55 PMID: 17129787
  64. Moesin expression is a marker of basal breast carcinomas.
    Int J Cancer. 2007 Oct 15;121(8):1779-85 PMID: 17594689
  65. The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis.
    Cancer Res. 2008 Oct 1;68(19):7711-7 PMID: 18829523
  66. Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers.
    Cancer Res. 2005 Nov 1;65(21):9751-61 PMID: 16266996
  67. VDAC2 inhibits BAK activation and mitochondrial apoptosis.
    Science. 2003 Jul 25;301(5632):513-7 PMID: 12881569
  68. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  69. Transcription factor EGR3 is involved in the estrogen-signaling pathway in breast cancer cells.
    J Mol Endocrinol. 2004 Jun;32(3):649-61 PMID: 15171706
  70. CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer.
    Mol Oncol. 2008 Dec;2(4):327-39 PMID: 19383354
  71. Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells.
    Cancer Res. 2006 Feb 15;66(4):2116-28 PMID: 16489012
  72. Profiling essential genes in human mammary cells by multiplex RNAi screening.
    Science. 2008 Feb 1;319(5863):617-20 PMID: 18239125
  73. Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors.
    Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12963-8 PMID: 12297621
  74. Differential regulation of human RecQ family helicases in cell transformation and cell cycle.
    Oncogene. 2000 Sep 28;19(41):4764-72 PMID: 11032027
  75. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage.
    Cancer Cell. 2007 Feb;11(2):175-89 PMID: 17292828
  76. Role of mammalian RAD51L2 (RAD51C) in recombination and genetic stability.
    J Biol Chem. 2002 May 31;277(22):19322-30 PMID: 11912211
  77. Regulation of microfilament reorganization and invasiveness of breast cancer cells by kinase dead p21-activated kinase-1.
    J Biol Chem. 2000 Apr 21;275(16):12041-50 PMID: 10766836
  78. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
    Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74 PMID: 11553815
  79. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.
    Cell. 1998 May 1;93(3):467-76 PMID: 9590180
  80. Human homologs of Schizosaccharomyces pombe rad1, hus1, and rad9 form a DNA damage-responsive protein complex.
    J Biol Chem. 1999 Jan 8;274(2):567-70 PMID: 9872989
  81. The druggable genome.
    Nat Rev Drug Discov. 2002 Sep;1(9):727-30 PMID: 12209152
  82. Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics.
    Breast Cancer Res. 2008;10(1):R10 PMID: 18241344
  83. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes.
    Cancer Cell. 2006 Dec;10(6):515-27 PMID: 17157791
  84. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
    Methods. 2001 Dec;25(4):402-8 PMID: 11846609
  85. A functional genomic screen identifies a role for TAO1 kinase in spindle-checkpoint signalling.
    Nat Cell Biol. 2007 May;9(5):556-64 PMID: 17417629
  86. Significance analysis of microarrays applied to the ionizing radiation response.
    Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21 PMID: 11309499
  87. Molecular and cellular analysis of basement membrane invasion by human breast cancer cells in Matrigel-based in vitro assays.
    Breast Cancer Res Treat. 1993;24(3):241-55 PMID: 8435479
  88. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer.
    Science. 1997 Aug 15;277(5328):965-8 PMID: 9252329
  89. CDC6: from DNA replication to cell cycle checkpoints and oncogenesis.
    Carcinogenesis. 2008 Feb;29(2):237-43 PMID: 18048387
  90. Structure of the human oestrogen-responsive gene pS2.
    Nucleic Acids Res. 1987 Feb 25;15(4):1401-14 PMID: 3822834
  91. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies.
    Cancer Cell. 2006 Dec;10(6):529-41 PMID: 17157792
  92. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers.
    PLoS Med. 2006 Mar;3(3):e47 PMID: 16417408
  93. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes.
    Cancer Cell. 2007 Aug;12(2):160-70 PMID: 17692807
  94. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland.
    J Cell Biol. 2007 Jan 1;176(1):19-26 PMID: 17190790
  95. Genome-wide analysis of DNA copy-number changes using cDNA microarrays.
    Nat Genet. 1999 Sep;23(1):41-6 PMID: 10471496
  96. Attenuation of adhesion-dependent signaling and cell spreading in transformed fibroblasts lacking protein tyrosine phosphatase-1B.
    J Biol Chem. 2001 Jul 13;276(28):25848-55 PMID: 11346638
  97. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation.
    Nat Cell Biol. 2007 Feb;9(2):201-9 PMID: 17187062
  98. Pieces of the puzzle: expressed sequence tags and the catalog of human genes.
    J Mol Med (Berl). 1997 Oct;75(10):694-8 PMID: 9382993
  99. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays.
    Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15623-8 PMID: 9861020
  100. Urokinase-type plasminogen activation in three human breast cancer cell lines correlates with their in vitro invasiveness.
    Clin Exp Metastasis. 1996 May;14(3):297-307 PMID: 8674284
  101. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds.
    PLoS Biol. 2004 Feb;2(2):E7 PMID: 14737219
  102. Spatial smoothing and hot spot detection for CGH data using the fused lasso.
    Biostatistics. 2008 Jan;9(1):18-29 PMID: 17513312
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0006146
Published
2009-07-03
Epub
2009-00-03
Pages
e6146
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2702084
Subset
IM
Grants
NCI NIH HHS · R01 CA097139 · United States
NCI NIH HHS · T32 CA009151 · United States
NCI NIH HHS · T32 CA009302 · United States
NCI NIH HHS · CA97139 · United States
External Links
PubMed source DOI: 10.1371/journal.pone.0006146 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2