Estrogen receptor-negative (ER -) breast cancers have limited treatment options and are associated with earlier relapses. Because glucocorticoid receptor (GR) signaling initiates antiapoptotic 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 premalignant 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 carrying out a meta-analysis of primary breast tumor gene expression from 1,378 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.
ASJC Scopus subject areas
- Cancer Research