Data from The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor Gene <i>BRCA1</i> through GABP Beta

Abstract

<div>Abstract<p>Loss of BRCA1 tumor suppressor function is a critical event in breast tumorigenesis. We have previously identified the stress hormone hydrocortisone as a negative regulator of <i>BRCA1</i> expression in nonmalignant mammary cells. Here, we have identified a direct role for the unliganded glucocorticoid receptor (GR) in <i>BRCA1</i> upregulation in the absence of hydrocortisone. The positive regulatory effect of GR is lost upon the addition of hydrocortisone. We have shown that GR interacts with the <i>BRCA1</i> promoter only in the absence of hydrocortisone, and that this interaction is mediated through the β-subunit of the <i>ets</i> transcription factor GA-binding protein (GABP) at the RIBS promoter element. GR and GABPβ interact in both coimmunoprecipitation and mammalian two-hybrid assays, and this interaction involves the <i>N</i>-terminal to central regions of both proteins. This work presents the first evidence of a ligand-independent role for GR as a positive regulator of gene expression, and loss of GR from the <i>BRCA1</i> promoter in response to stress hormones leads to decreased <i>BRCA1</i> expression. Because low levels of <i>BRCA1</i> have been implicated in the development of sporadic breast cancer, this may represent a novel mechanism through which prolonged stress signaling increases breast cancer risk. <i>Mol Cancer Res; 10(4); 558–69. ©2012 AACR</i>.</p></div>