An AIB1 isoform rewires glucocorticoid receptor signaling to promote TNBC progression.

The role of glucocorticoid receptor (GR) signaling in triple-negative breast cancer (TNBC) progression remains poorly defined. Here, we describe a GR-dependent mechanism driving TNBC invasion, mediated by the presence of a subpopulation of cancer cells that express an N-terminal truncated splice isoform of the nuclear receptor coactivator AIB1. Invasion was driven through direct contact of this subpopulation with neighboring cancer cells, and suppressed by GR antagonists or depletion of GR. Crosstalk between the AIB1 isoform-expressing cells and full-length AIB1-expressing cells triggered enhanced GR activation, GR signaling, and distinct patterns of AIB1 genomic engagement. Notably, GR signaling selectively activated pathways driven by Myc in the AIB1 isoform-expressing population, and the reduction of Myc reduced invasion. These findings identify the emergence of an AIB1 isoform-expressing subpopulation as a key mechanism driving progression in TNBC and suggest sensitivity to GR-targeted therapies.