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Integrated Profiling of Basal and Luminal Breast Cancers

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Integrated Profiling of Basal and Luminal Breast Cancers Research Article Integrated Profiling of Basal and Luminal Breast Cancers Jose´Ade´laı¨de,1 Pascal Finetti,1 Ismahane Bekhouche,1 Laetitia Repellini,1 Jeannine Geneix,1 Fabrice Sircoulomb,1 Emmanuelle Charafe-Jauffret,1,2,4 Nathalie Cervera,1 Je´roˆme Desplans,5 Daniel Parzy,5 Eric Schoenmakers,6 Patrice Viens,3,4 Jocelyne Jacquemier,1,2 Daniel Birnbaum,1 Franc¸ois Bertucci,1,3,4 and Max Chaffanet1 1Marseille Cancer Research Center, Institut Paoli-Calmettes and UMR599 Institut National de la Sante´et de la Recherche Me´dicale, Department of Molecular Oncology, 2Department of Biopathology, and 3Department of Medical Oncology, Institut Paoli-Calmettes; 4Universite´delaMe´diterrane´e; 5Institut de Me´decineTropicale du Service de Sante´des Arme´es,Unite´de Recherche en Pharmacologie et Physiopathologie Parasitaire, Marseille, France; and 6Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands Abstract these definitions allow a better management of the disease (1). Five Basal and luminal are two molecular subtypes of breast major breast cancer molecular subtypes (luminal A and B, basal, cancer with opposite histoclinical features. We report a com- ERBB2 overexpressing, and normal-like) have been identified (2–5). bined, high-resolution analysis of genome copy number and They are associated with different prognosis. Luminal A breast gene expression in primary basal and luminal breast cancers. cancers express hormone receptors, have an overall good prognosis, First, we identified and compared genomic alterations in 45 and can be treated by hormone therapy. ERBB2-overexpressing basal and 48 luminal tumors by using 244Koligonucleotide breast cancers have a poor prognosis and are treated by targeted array comparative genomic hybridization (aCGH). We found therapy using trastuzumab or lapatinib (see ref. 6 for review). No various genome gains and losses and rare high-level gene specific therapy is available for the other subtypes, although the amplifications that may provide therapeutic targets. We show prognosis of basal and luminal B tumors is poor. that gain of 10p is a new alteration in basal breast cancer Progress can be made in several directions. First, by identifying, and that a subregion of the 8p12 amplification is specific among good prognosis tumors such as luminal A breast cancers, of luminal tumors. Rare high-level amplifications contained the cases that will relapse and metastasize. Second, by developing new drugs that will allow a better management of poor-prognosis BCL2L2, CCNE, EGFR, FGFR2, IGF1R, NOTCH2, and PIK3CA. Potential gene breaks involved ETV6 and FLT3. Second, we breast cancers, such as basal tumors. The identification of new analyzed both aCGH and gene expression profiles for 42 basal markers and therapeutic targets is necessary to meet these objec- and 32 luminal breast cancers. The results support the tives. This relies on the study of tumor samples at the genomic existence of specific oncogenic pathways in basal and luminal (7–14), gene expression (2, 4, 15, 16), or proteomic (17–19) levels. breast cancers, involving several potential oncogenes and We have established here the genomic and gene expression tumor suppressor genes (TSG). In basal tumors, 73 candidate profiles of a series of breast cancer samples by using high- oncogenes were identified in chromosome regions 1q21-23, resolution array comparative genomic hybridization (aCGH) and 10p14, and 12p13 and 28 candidate TSG in regions 4q32-34 DNA microarrays, respectively. We have focused our analysis on and 5q11-23. In luminal breast cancers, 33 potential onco- two breast cancer subtypes with overall opposite features: luminal and basal. genes were identified in 1q21-23, 8p12-q21, 11q13, and 16p12- 13 and 61 candidate TSG in 16q12-13, 16q22-24, and 17p13. À À HORMAD1 (P =6.5Â 10 5) and ZNF703 (P =7Â 10 4) were Materials and Methods the most significant basal and luminal potential oncogenes, Breast cancer samples. Tumor tissues were collected from 202 patients respectively. Finally, among 10p candidate oncogenes asso- with invasive adenocarcinoma who underwent initial surgery at the Institut ciated with basal subtype, we validated CDC123/C10orf7 pro- Paoli-Calmettes (Marseilles, France) between 1992 and 2004 (from a cohort tein as a basal marker. [Cancer Res 2007;67(24):11565–75] of 1,185 patients with frozen tumor sample). Each patient gave written informed consent and the study was approved by our institutional review Introduction board. Samples were macrodissected and frozen in liquid nitrogen within 30 min of removal. Several sets of tumors were studied. Gene expression Breast cancer is a heterogeneous disease whose evolution is was analyzed on a set of 202 tumors. Gene expression and genome difficult to predict. Consequently, treatment is not as adapted as it profilings were established on a subset of 74 tumors (42 basal and should be. Breast cancer can be defined at the clinical, histologic, 32 luminal A; as defined in ref. 4) for which RNA and DNA samples were cellular, and molecular levels. Progress and efforts to integrate both available. Genome profiles were established on 93 tumors, including these 74 tumors and an additional set of 19 cases selected from immuno- histochemical data on estrogen receptor (ER), progesterone receptor (PR), À À À Note: Supplementary data for this article are available at Cancer Research Online ERBB2, and other basal and luminal markers (20): 2 ER /PR /ERBB2 À (http://cancerres.aacrjournals.org/). (‘‘triple negative’’) and 17 ER+/ERBB2 (21) tumors associated with basal- J. Ade´laı¨de and P. Finetti contributed equally to this work. like and luminal-like immunohistochemical phenotypes, respectively. Requests for reprints: Max Chaffanet, Department of Molecular Oncology, Institut Paoli-Calmettes, 232 Bd. Sainte Marguerite, 13009 Marseille, France. Phone: 33-4-91-22- Although a third of the luminal tumors were not profiled on expression 34-77; Fax: 33-4-91-22-35-44; E-mail: [email protected] or Daniel microarrays, immunohistochemical-based phenotypes were established for Birnbaum, UMR599 Institut National de la Sante et de la Recherche Medicale, 27 all studied tumors: 98% and 88% of the luminal samples used in this study Bd. Leı¨Roure, 13009 Marseille, France. Phone: 33-4-91-75-84-07; E-mail: birnbaum@ were ER and PR positive, respectively (see Supplementary Table S1). The set marseille.inserm.fr. I2007 American Association for Cancer Research. studied by aCGH thus comprised 44 basal and 49 luminal tumors (mainly doi:10.1158/0008-5472.CAN-07-2536 luminal A tumors). All tumor sections were reviewed by two pathologists www.aacrjournals.org 11565 Cancer Res 2007; 67: (24). December 15, 2007 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2007 American Association for Cancer Research. Cancer Research (J. Jacquemier and E. Charafe-Jauffret) before analysis. All specimens probe locus as the proportion of samples showing an aberration therein. contained >60% of tumor cells (as assessed before RNA extraction using Alteration frequencies were evaluated by Fisher’s exact test and false frozen sections adjacent to the profiled samples). The main histoclinical discovery rate (FDR) was applied to correct the multiple testing characteristics of samples are listed in Supplementary Table S1. Immuno- hypothesis (33). histochemical data included status for the following: ER, PR, and P53 Combined genomic and expression data analysis. For each gene, data (positivity cutoff value of 1%); ERBB2 (0–3+ score, DAKOHercepTest kit from two corresponding probe sets (Agilent and Affymetrix) were scoring guidelines, with >1+ defined as positive); and Ki67 (positivity cutoff compared. Frequencies of combined alterations, overexpression associated value of 20%). Among basal tumors were 14 medullary breast cancers (MBC) with amplification and the opposite, were evaluated. Data were then log2 defined on Ridolfi’s criteria (22). MBCs displayed characteristics similar to transformed and submitted to the Cluster program (30) using data median- series in literature with 100% of samples Scarff-Bloom-Richardson grade 3, centered on genes, Pearson correlation as similarity metric, and centroid ER negative, ERBB2 negative, Ki67 positive, and 49% P53 positive. After linkage clustering. Results were displayed using the TreeView program (30).7 surgery, patients were treated using a multimodal approach according to Fluorescence in situ hybridization analysis. Fluorescence in situ standard guidelines. Eleven normal breast tissue samples pooled in four hybridization (FISH) analysis on tissue microarrays using bacterial artificial RNA samples were also profiled on gene expression microarrays. chromosome (BAC) probes has been described previously (34). DNA and RNA extraction. DNA and RNA were extracted from frozen Immunohistochemistry on breast cancer tissues. Anti-epidermal samples by using guanidium isothiocynanate and cesium chloride gradient growth factor receptor (EGFR) antibody (clone 31G7, 1:20 dilution; Zymed as described previously (23). RNA integrity was controlled on Agilent Laboratories) and anti-CDC123 antibody (clone 4B9, 1:300 dilution; Abnova Bioanalyzer (Agilent Technologies). Corp.) were used for immunohistochemistry. A pepsin treatment was done Gene expression profiling with DNA microarrays. Expression profiles on tissue sections for 30 min before immunohistochemistry with EGFR were established for 202 breast cancers
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