Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand-inducible growth state

Despite the role of the estrogen receptor alpha (ER alpha) pathway as a key growth driver for breast cells, the phenotypic consequence of exogenous introduction of ER alpha into ER alpha-negative cells paradoxically has been growth inhibition. We mapped the binding profiles of ER alpha and its interacting transcription factors (TFs), FOXA1 and GATA3 in MCF-7 breast carcinoma cells, and observed that these three TFs form a functional enhanceosome that regulates the genes driving core ER alpha function and cooperatively modulate the transcriptional networks previously ascribed to ER alpha alone. We demonstrate that these enhanceosome occupied sites are associated with optimal enhancer characteristics with highest p300 co-activator recruitment, RNA Pol II occupancy, and chromatin opening. Most importantly, we show that the transfection of all three TFs was necessary to reprogramme the ER alpha-negative MDA-MB-231 and BT-549 cells to restore the estrogen-responsive growth resembling estrogen-treated ER alpha-positive MCF-7 cells. Cumulatively, these results suggest that all the enhanceosome components comprising ER alpha, FOXA1, and GATA3 are necessary for the full repertoire of cancer-associated effects of the ER alpha. Molecular Systems Biology 7: 526; published online 30 August 2011; doi:10.1038/msb.2011.59