How different are luminal A and basal breast cancers?

Heterogeneity of breast cancer makes its evolution difficult to predict, and its treatment far from being optimal. At least 5 main molecular subtypes exist. Two major subtypes are luminal A and basal subtypes, which have opposite features, notably survival. To characterize these 2 subtypes better, with the hope of better understanding their different biology and clinical outcome, we have profiled a series of 138 tumours (80 luminal A and 58 basal) using Affymetrix whole‐genome DNA microarrays. We have identified 5,621 probe sets as differentially expressed between the 2 subtypes in our series. These differences were validated in 6 independent public series (more than 600 tumours) profiled using different DNA microarrays platforms. Analysis of functions and pathways related to these probe sets, and the extent of the observed differences, confirmed that the 2 subtypes represent very distinct entities. Genes associated with proliferation, cell cycle, cell motility, angiogenesis, and NFkB signalling were overexpressed in basal tumours. Genes involved in fatty acid metabolism, TGFB signalling, and oestrogen receptor (ER) signalling were overexpressed in luminal A samples. Half of the genes overexpressed in luminal tumours contained ER‐binding sites. The number of differentially expressed genes was as high as the set of genes discriminating 2 cancers of different anatomical origin (breast and colon) or discriminating acute myeloid and lymphoid leukaemia. We provide a comprehensive list of genes/pathways that define potential diagnostic, prognostic and therapeutic targets for these 2 subtypes, which should be treated differently given the profound differences observed at the molecular level. © 2008 Wiley‐Liss, Inc.

[1]  E. Taubøll,et al.  Antiepileptic drugs inhibit cell growth in the human breast cancer cell line MCF7 , 2004, Molecular and Cellular Endocrinology.

[2]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[3]  P. Sismondi,et al.  FGFRI and PLAT genes and DNA amplification at 8p 12 in breast and ovarian cancers , 1993, Genes, chromosomes & cancer.

[4]  G. Lenoir,et al.  Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. , 2006, Cancer research.

[5]  F. Stossi,et al.  Whole-Genome Cartography of Estrogen Receptor α Binding Sites , 2007, PLoS genetics.

[6]  Fei Huang,et al.  Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. , 2007, Cancer research.

[7]  S. Ramaswamy,et al.  Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. , 2002, The Journal of clinical investigation.

[8]  C. Sotiriou,et al.  Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? , 2007, Nature Reviews Cancer.

[9]  C. Caldas,et al.  Molecular classification and molecular forecasting of breast cancer: ready for clinical application? , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  G. Lenoir,et al.  Acetyl-CoA Carboxylase α Is Essential to Breast Cancer Cell Survival , 2006 .

[11]  Daniel Birnbaum,et al.  Basal and luminal breast cancers: basic or luminous? (review). , 2004, International journal of oncology.

[12]  N. Rosen,et al.  The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. , 2001, Cancer research.

[13]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[14]  T. Sørlie,et al.  Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms , 2006, BMC Genomics.

[15]  K. Altundağ.  Primary breast cancer phenotypes associated with propensity for central nervous system metastases , 2006, Cancer.

[16]  T. Poggio,et al.  Multiclass cancer diagnosis using tumor gene expression signatures , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[19]  Daniel Birnbaum,et al.  Integrated profiling of basal and luminal breast cancers. , 2007, Cancer research.

[20]  R. Bataille,et al.  Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease. , 2003, Blood.

[21]  Z Chen,et al.  Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Yoav Benjamini,et al.  Identifying differentially expressed genes using false discovery rate controlling procedures , 2003, Bioinform..

[24]  S. Bailey,et al.  Nuclear factor-kappaB activation: a molecular therapeutic target for estrogen receptor-negative and epidermal growth factor receptor family receptor-positive human breast cancer. , 2007, Molecular cancer therapeutics.

[25]  Charles M. Perou,et al.  A Comparison of Gene Expression Signatures from Breast Tumors and Breast Tissue Derived Cell Lines , 2002, Disease markers.

[26]  C. Takimoto,et al.  Safety and anti-tumor activity of sorafenib (Nexavar®) in combination with other anti-cancer agents: a review of clinical trials , 2008, Cancer Chemotherapy and Pharmacology.

[27]  R. Kiessling,et al.  Her-2/neu as a paradigm of a tumor-specific target for therapy. , 2004, Breast disease.

[28]  S. Vacher,et al.  Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach. , 2006, Endocrine-related cancer.

[29]  F. Melsen,et al.  The prognostic value of oncogenic antigen 519 (OA‐519) expression and proliferative activity detected by antibody MIB‐I in node‐negative breast cancer , 1995, The Journal of pathology.

[30]  Daniel Birnbaum,et al.  How basal are triple‐negative breast cancers? , 2008, International journal of cancer.

[31]  C. Perou,et al.  Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. , 2006, JAMA.

[32]  J. Foekens,et al.  Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer , 2005, The Lancet.

[33]  S. Hilsenbeck,et al.  Primary breast cancer phenotypes associated with propensity for central nervous system metastases , 2006, Cancer.

[34]  L. Trusolino,et al.  Scatter-factor and semaphorin receptors: cell signalling for invasive growth , 2002, Nature Reviews Cancer.

[35]  Leonard D. Goldstein,et al.  MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype , 2007, Genome Biology.

[36]  Daniel Birnbaum,et al.  Gene expression profiling identifies molecular subtypes of inflammatory breast cancer. , 2005, Cancer research.

[37]  L. V. van't Veer,et al.  Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. , 2006, Journal of the National Cancer Institute.

[38]  Clifford A. Meyer,et al.  Genome-wide analysis of estrogen receptor binding sites , 2006, Nature Genetics.

[39]  Van,et al.  A gene-expression signature as a predictor of survival in breast cancer. , 2002, The New England journal of medicine.

[40]  Daniel Birnbaum,et al.  ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. , 2007, Cell stem cell.

[41]  J. Welsh,et al.  Molecular classification of human carcinomas by use of gene expression signatures. , 2001, Cancer research.

[42]  F. Bertucci,et al.  Moesin expression is a marker of basal breast carcinomas , 2007, International journal of cancer.

[43]  E. Devilard,et al.  Identification of new classes among acute myelogenous leukaemias with normal karyotype using gene expression profiling , 2004, Oncogene.

[44]  H. Nakshatri,et al.  Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion , 2007, Oncogene.

[45]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[46]  J. Eeckhoute,et al.  Positive cross-regulatory loop ties GATA-3 to estrogen receptor alpha expression in breast cancer. , 2007, Cancer research.

[47]  Amy V Kapp,et al.  Discovery and validation of breast cancer subtypes , 2006, BMC Genomics.

[48]  J. Ross,et al.  Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  E. Lander,et al.  MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia , 2002, Nature Genetics.

[50]  B. Rayet,et al.  Aberrant rel/nfkb genes and activity in human cancer , 1999, Oncogene.

[51]  R. Eils,et al.  Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[52]  William E. Hughes,et al.  Site-Directed Perturbation of Protein Kinase C- Integrin Interaction Blocks Carcinoma Cell Chemotaxis , 2002, Molecular and Cellular Biology.

[53]  J. Downing,et al.  Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. , 2003, Blood.

[54]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[55]  A. Nobel,et al.  The molecular portraits of breast tumors are conserved across microarray platforms , 2006, BMC Genomics.

[56]  I. Ellis,et al.  c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer , 1998, Oncogene.

[57]  S. Badve,et al.  FOXA1 as a therapeutic target for breast cancer , 2007, Expert opinion on therapeutic targets.

[58]  Daniel Birnbaum,et al.  Prognosis and Gene Expression Profiling of 20q13-Amplified Breast Cancers , 2006, Clinical Cancer Research.

[59]  J. Reis-Filho,et al.  Forkhead box A1 expression in breast cancer is associated with luminal subtype and good prognosis , 2007, Journal of Clinical Pathology.

[60]  Johan Eide,et al.  Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[61]  Arvind K Pandey,et al.  Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells. , 2006, Cancer research.

[62]  K. Fujikawa,et al.  The Ets‐1 and Ets‐2 transcription factors activate the promoters for invasion‐associated urokinase and collagenase genes in response to epidermal growth factor , 1998, International journal of cancer.

[63]  M. Malumbres,et al.  Targeting cell cycle kinases for cancer therapy. , 2007, Current medicinal chemistry.

[64]  M. Kinch,et al.  Overexpression and functional alterations of the EphA2 tyrosine kinase in cancer , 2004, Clinical & Experimental Metastasis.

[65]  P. Dam,et al.  Identification of cell-of-origin breast tumor subtypes in inflammatory breast cancer by gene expression profiling , 2006, Breast Cancer Research and Treatment.

[66]  H. Nakshatri,et al.  NF-κ B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4* , 2003, Journal of Biological Chemistry.

[67]  M. Rubin,et al.  Integrative biology of prostate cancer progression. , 2006, Annual review of pathology.

[68]  Pierre Baldi,et al.  A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes , 2001, Bioinform..

[69]  C. Perou,et al.  AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer. , 2005, The Journal of clinical investigation.

[70]  Javier A Menendez,et al.  Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators? , 2006, Endocrinology.

[71]  J. Bergh,et al.  Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  Daohai Zhang,et al.  Proteomic Study Reveals That Proteins Involved in Metabolic and Detoxification Pathways Are Highly Expressed in HER-2/neu-positive Breast Cancer* , 2005, Molecular & Cellular Proteomics.

[73]  J. Downing,et al.  Gene Expression Profiling of Pediatric Acute Myelogenous Leukemia Materials and Methods , 2022 .

[74]  I. Ellis,et al.  Clinical Value of Epidermal Growth Factor Receptor Expression in Primary Breast Cancer , 2005, Advances in anatomic pathology.

[75]  J. Stec,et al.  A single-gene biomarker identifies breast cancers associated with immature cell type and short duration of prior breastfeeding. , 2005, Endocrine-related cancer.

[76]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[77]  Philip M. Long,et al.  Breast cancer classification and prognosis based on gene expression profiles from a population-based study , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[78]  F. Kuhajda,et al.  Fatty acid synthase and cancer: new application of an old pathway. , 2006, Cancer research.

[79]  N. Pryer,et al.  Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. , 2003, Molecular cancer therapeutics.

[80]  F. Bertucci,et al.  Gene expression profiling of breast cell lines identifies potential new basal markers , 2006, Oncogene.

[81]  A. Nobel,et al.  Concordance among Gene-Expression – Based Predictors for Breast Cancer , 2011 .

[82]  Puay Hoon Tan,et al.  Conservation of Breast Cancer Molecular Subtypes and Transcriptional Patterns of Tumor Progression Across Distinct Ethnic Populations , 2004, Clinical Cancer Research.

[83]  Jérôme Eeckhoute,et al.  Positive Cross-Regulatory Loop Ties GATA-3 to Estrogen Receptor α Expression in Breast Cancer , 2007 .

[84]  P. Morin,et al.  Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. , 2002, Experimental cell research.

[85]  G. Sherlock.  Analysis of large-scale gene expression data. , 2000, Current opinion in immunology.

[86]  Heng Tao Shen,et al.  Principal Component Analysis , 2009, Encyclopedia of Biometrics.

[87]  O. Barbash,et al.  Expression of Angiogenic Factors Vascular Endothelial Growth Factor and Interleukin-8/CXCL8 Is Highly Responsive to Ambient Glutamine Availability , 2004, Cancer Research.

[88]  Christian A. Rees,et al.  Systematic variation in gene expression patterns in human cancer cell lines , 2000, Nature Genetics.

[89]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[90]  G. Favre,et al.  Farnesyl-transferase inhibitor R115,777 enhances tamoxifen inhibition of MCF-7 cell growth through estrogen receptor dependent and independent pathways , 2005, Breast Cancer Research.

[91]  L. Chow,et al.  Sunitinib: from rational design to clinical efficacy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[92]  F. Bertucci,et al.  Gene Expression Profiling for Molecular Characterization of Inflammatory Breast Cancer and Prediction of Response to Chemotherapy , 2004, Cancer Research.

[93]  Wolfgang Heller,et al.  Triple-negative breast cancer: therapeutic options. , 2007, The Lancet. Oncology.

[94]  D. Yu,et al.  Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors , 2006, Oncogene.

[95]  J. Dering,et al.  Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro , 2007, Breast Cancer Research and Treatment.