Investigating tamoxifen resistance in the luminal B estrogen receptor positive breast cancer subtype: Tailoring treatment in hormone responsive breast cancer

Abstract

10603 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 (J Clin Onc, in press). 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 global 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 and may contribute to TAM resistance in this subtype. To validate this hypothesis, 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 TAM resistant luminal B subtype. In this group, targeting activated HER2 signaling may be a helpful treatment strategy despite the lack of HER2 overexpression. Our data suggests 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. No significant financial relationships to disclose.