BMC Medical Genomics Volume 2
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 Research articleGene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancerSherene Loi1,2,3 , Christos Sotiriou2 , Benjamin Haibe-Kains2 , Francoise Lallemand2 , Nelly M Conus1 , Martine J Piccart2 , Terence P Speed4 and Grant A McArthur1,3  1Department of Research, Molecular Oncology Lab, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 2Translational and Functional Genomics Unit, Jules Bordet Institute, Brussels, Belgium 3Department of Medicine, St. Vincent Hospital, University of Melbourne, Victoria, Australia 4Department of Bioinformatics, Walter and Eliza Hall Institute, Parkville, Victoria, Australia author email corresponding author email
BMC Medical Genomics 2009,
2:37doi:10.1186/1755-8794-2-37 Abstract
Background
Within estrogen receptor-positive breast cancer (ER+ BC), the expression levels of proliferation-related genes can define two clinically distinct molecular subtypes. When treated with adjuvant tamoxifen, those ER+ BCs that are lowly proliferative have a good prognosis (luminal-A subtype), however the clinical outcome of those that are highly proliferative is poor (luminal-B subtype).
Methods
To investigate the biological basis for these observations, gene set enrichment analysis (GSEA) was performed using microarray data from 246 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. To create an in vitro model of growth factor (GF) signaling activation, MCF-7 cells were treated with heregulin (HRG), an HER3 ligand.
Results
We found that a gene set linked to GF signaling was significantly enriched in the luminal-B tumors, despite only 10% of samples over-expressing HER2 by immunohistochemistry. To determine the biological significance of this observation, MCF-7 cells were treated with HRG. These cells displayed phosphorylation of HER2/3 and downstream ERK and S6. Treatment with HRG overcame tamoxifen-induced cell cycle arrest with higher S-phase fraction and increased anchorage independent colony formation. Gene expression profiles of MCF-7 cells treated with HRG confirmed enrichment of the GF signaling gene set and a similar proliferative signature observed in human ER+ BCs resistant to tamoxifen.
Conclusion
These data demonstrate that activation of GF signaling pathways, independent of HER2 over-expression, could be contributing to the poor prognosis of the luminal-B ER+ BC subtype. |