Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer

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• 作者：Sherene Loi (1) (2) (3)
  Christos Sotiriou (2)
  Benjamin Haibe-Kains (2)
  Francoise Lallemand (2)
  Nelly M Conus (1)
  Martine J Piccart (2)
  Terence P Speed (4)
  Grant A McArthur (1) (3)
  
• 刊名：BMC Medical Genomics
• 出版年：2009
• 出版时间：December 2009
• 年：2009
• 卷：2
• 期：1
• 全文大小：886KB
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• 作者单位：Sherene Loi (1) (2) (3)
  Christos Sotiriou (2)
  Benjamin Haibe-Kains (2)
  Francoise Lallemand (2)
  Nelly M Conus (1)
  Martine J Piccart (2)
  Terence P Speed (4)
  Grant A McArthur (1) (3)
  
  1. Department of Research, Molecular Oncology Lab, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  2. Translational and Functional Genomics Unit, Jules Bordet Institute, Brussels, Belgium
  3. Department of Medicine, St. Vincent Hospital, University of Melbourne, Victoria, Australia
  4. Department of Bioinformatics, Walter and Eliza Hall Institute, Parkville, Victoria, Australia
  
• ISSN：1755-8794

文摘

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.