Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer
Deng Pan, Masha Kocherginsky, Suzanne D Conzen, Deng Pan, Masha Kocherginsky, Suzanne D Conzen
Abstract
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.
Figures
![Figure 1. Relative genomic locations of GR…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3514452/bin/nihms320652f1.jpg)
![Figure 2. Relative percentage of glucocorticoid-regulated genes…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3514452/bin/nihms320652f2.jpg)
![Figure 3. Kaplan-Meier estimates of relapse-free survival…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3514452/bin/nihms320652f3.jpg)
![Figure 4. Genes and gene expression pathways…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3514452/bin/nihms320652f4.jpg)
Source: PubMed