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

• Huvudupphovsmän: Conus Nelly M (Författare, medförfattare), Lallemand Francoise (Författare, medförfattare), Haibe-Kains Benjamin (Författare, medförfattare), Sotiriou Christos (Författare, medförfattare), Loi Sherene (Författare, medförfattare), Piccart Martine J (Författare, medförfattare), Speed Terence P (Författare, medförfattare), McArthur Grant A (Författare, medförfattare)
• Materialtyp: Bok
• Publicerad: BMC, 2009-06-01T00:00:00Z.
• Ämnen: article
• Länkar: Connect to this object online.

Sammanfattning

<p>Abstract</p> <p>Background</p> <p>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).</p> <p>Methods</p> <p>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 <it>in vitro </it>model of growth factor (GF) signaling activation, MCF-7 cells were treated with heregulin (HRG), an HER3 ligand.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p>

Beskrivning

10.1186/1755-8794-2-37
1755-8794