Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1

The estrogen receptor (ER) is an important regulator of growth and differen tiation of breast epithelium. Transactivation by ER depends on a leucine-ri ch motif, which constitutes a ligand-regulated binding site for steroid rec eptor coactivators (SRCs). Cyclin D1 is frequently amplified in breast canc er and can activate ER through direct binding. We show here that cyclin D1 also interacts in a ligand-independent fashion with coactivators of the SRC -1 family through a motif that resembles the leucine-rich coactivator bindi ng motif of nuclear receptors. By acting as a bridging factor between ER an d SRCs, cyclin D1 can recruit SRC-family coactivators to ER in the absence of ligand. A cyclin D1 mutant that binds to ER but fails to recruit coactiv ators preferentially interferes with ER activation in breast cancer cells t hat have high levels of cyclin D1. These data support that cyclin D1 contri butes significantly to ER activation in breast cancers in which the protein is overexpressed. Our present results reveal a novel route of coactivator recruitment to ER and establish a direct role for cyclin D1 in regulation o f transcription.