Identification and validation of an ERBB2 gene expression signature in breast cancers.
ERBB2 is a transmembrane tyrosine kinase receptor encoded by a gene located in chromosome region 17q12. Overexpression of ERBB2, generally by way of gene amplification, plays a role in mammary oncogenesis. This alteration can be overcome by use of the humanized monoclonal antibody trastuzumab (Herceptin). Accurate determination of ERBB2 status is required for appropriate use of this targeted therapy and is currently analysed by immunohistochemistry (IHC) on tissue sections and/or fluorescence in situ hybridisation (FISH) on interphase chromosomes. We have studied the gene expression profiles of a series of 213 breast tumours and 16 breast cancer cell lines with known ERBB2 status, using Ipsogen's DiscoveryChip microarrays with approximately 9000 cDNAs. We have identified 36 genes and expressed sequence tags that were differentially expressed in tumours and in cell lines with and without ERBB2 protein overexpression. This ERBB2-specific gene expression signature (GES) contained 29 overexpressed genes including the ERBB2 gene itself, five genes located in its immediate vicinity on 17q12, non-17q genes such as GATA4 and eight downregulated genes including oestrogen receptor alpha (ER). Some correlations were validated at the protein level using IHC on tissue microarrays. The GES was able to distinguish ERBB2-negative and -positive cancer samples, as well as FISH-negative and FISH-positive ERBB2 2+ IHC samples.
Bertucci
François
F
Département d'Oncologie Moléculaire, Institut Paoli-Calmettes and UMR119 Inserm, IFR57, and Faculté de Médecine, Université de la Méditerranée, Marseille, France.
Borie
Nathalie
N
Ginestier
Christophe
C
Groulet
Agnès
A
Charafe-Jauffret
Emmanuelle
E
Adélaïde
José
J
Geneix
Jeannine
J
Bachelart
Loïc
L
Finetti
Pascal
P
Koki
Alane
A
Hermitte
Fabienne
F
Hassoun
Jacques
J
Debono
Stéphane
S
Viens
Patrice
P
Fert
Vincent
V
Jacquemier
Jocelyne
J
Birnbaum
Daniel
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D015536:Down-Regulation; D020224:Expressed Sequence Tags; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D021141:Nucleic Acid Amplification Techniques; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068878:Trastuzumab