Investigating tamoxifen resistance in
the luminal B estrogen receptor positive breast cancer subtype:
Tailoring treatment in hormone responsive breast cancer.
Loi S, Sotiriou C, Haibe-Kains B, Lallemand F, Conus N, Piccart MJ, Speed T and McArthur GA
Background: We recently
reported that the two estrogen receptor (ER)-positive breast cancer
(BC) molecular subtypes can be defined by their expression of
proliferation genes using a gene expression index (GGI): the luminal A
and B subtypes have low and high levels respectively. When treated with
adjuvant tamoxifen, luminal A tumors have a good prognosis, however the
clinical outcome of the luminal B subtype was poor. This study aimed to
explain the biological basis for these observations using gene
expression profiling and an in vitro model of ER+ BC.
Methods: 246 ER+ BC samples
from women treated with adjuvant tamoxifen monotherapy were analyzed
with Affymetrix gene expression arrays and evaluated using gene set
enrichment analysis (GSEA). ER+ MCF-7 BC cells (control) treated with
tamoxifen (TAM) and heregulin (HRG) were used to investigate molecular
pathways identified using GSEA.
Results: We found that a gene set suggesting ERBB2 pathway
activation was significantly enriched in the luminal B subtype
(p=0.02). Only 10% of samples overexpressed HER2 by
immunohistochemistry, suggesting that activation of HER2 signaling
pathways is independent of HER2 overexpression in this subtype. MCF-7
cell-lines were treated with HRG (HRG-MCF7) to create a model of ERBB2
pathway activation. HRG-MCF7 cells displayed phosphorylation of HER2/3
without HER2 overexpression. Treatment with HRG overcame TAM induced
cell cycle arrest with higher S-phase fraction (p<0.01) and
increased anchorage-independent colony formation (p<0.01). Gene
expression profiling confirmed significant enrichment of the ERBB2 gene
set (p<0.01) and higher GGI levels (p=0.02) in HRG-MCF7 cells
compared with control.
Conclusions: HRG-MCF7 cells may
be useful as an in vitro model of the luminal B subtype. In this group,
targeting activated HER2 signaling may be a helpful treatment strategy
despite the lack of HER2 overexpression. Our data suggest that agents
like lapatinib may be effective only in the luminal B and not the
luminal A tumors, demonstrating the importance of stratifying by
subtype in future clinical trials of ER+ disease.