Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors.
BACKGROUND
BRCA1- and BRCA2-associated tumors appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers.


METHODS
Breast tumor RNAs from 7 BRCA1 and 6 BRCA2 mutation carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors.


RESULTS
Genes more highly expressed in BRCA1-associated tumors included stathmin, osteopontin, TGFbeta2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. BRCA2-associated cancers were characterized by the higher relative expression of FGF1 and FGFR2. FGFR2 protein was also more highly expressed in BRCA2-associated cancers (P = 0.004).


CONCLUSIONS
BRCA1-associated tumours demonstrated increased expression of component genes of the Notch and TGFbeta pathways whereas the higher expression of FGFR2 and FGF1 in BRCA2-associated cancers suggests the existence of an autocrine stimulatory loop.
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
Anita L
AL
Bane
Dushanthi
D
Pinnaduwage
Sarah
S
Colby
Michael
M
Reedijk
Sean E
SE
Egan
Shelley B
SB
Bull
Frances P
FP
O'Malley
Irene L
IL
Andrulis
D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000235:genetics*; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology; D050777:Stathmin / Q000096:biosynthesis / Q000235:genetics; D046888:Tissue Array Analysis; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000235:genetics
D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D050777:Stathmin; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2; D016220:Fibroblast Growth Factor 1; D053495:Osteopontin; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2