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

Abstract

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.