Gene expression profiling
identifies activated growth factor signaling in poor prognosis
(Luminal-B) estrogen receptor positive breast cancer
Loi S, Sotiriou C, Haibe-Kains B, Lallemand F, Conus NM, Piccart MJ, Speed TP, McArthur GA
Background: Within estrogen
receptor-positive breast cancer (ER+BC), the level expression of
proliferation 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 overexpressing 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+ breast tumors resistant to
tamoxifen.
Conclusions: 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. Activated growth factor signaling in
Luminal-B ER+ breast cancer