Estrogen-negative (ER-) breast cancers have limited treatment options and are associated with earlier relapses. Because glucocorticoid receptor (GR) signaling initiates anti-apoptotic pathways in ER- breast cancer cells, we hypothesized that activation of these pathways might be associated with poor prognosis in ER- disease. Here we report findings from a genome-wide study of GR transcriptional targets in a pre-malignant ER- cell line model of early breast cancer (MCF10A-Myc) and in primary early-stage ER- human tumors. Chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) coupled to time course expression profiling led us to identify epithelial-to-mesenchymal transition (EMT) pathways as an important aspect associated with GR activation. We validated these findings by performing a meta-analysis of primary breast tumor gene expression from 1378 early stage breast cancer patients with long-term clinical follow-up, confirming that high levels of GR expression significantly correlated with shorter relapse-free survival in ER- patients who were treated or untreated with adjuvant chemotherapy. Notably, in ER+ breast cancer patients, high levels of GR expression in tumors were significantly associated with better outcome relative to low levels of GR expression. Gene expression analysis revealed that ER- tumors expressing high GR levels exhibited differential activation of EMT, cell adhesion and inflammation pathways. Our findings suggest a direct transcriptional role for GR in determining the outcome of poor-prognosis ER- breast cancers.

PMID: 21868756 [PubMed - as supplied by publisher] Source: National Library of Medicine.