title: Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer.
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.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Deng
authors.initials: D
authors.lastname: Pan
authors.forename: Masha
authors.initials: M
authors.lastname: Kocherginsky
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Conzen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; C497713:NR3C1 protein, human; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid