DECIPHERING THE ENHANCEOSOME-MEDIATED TRANSCRIPTIONAL ACTIVATION AND CELL PROLIFERATION IN BREAST CANCER

Abstract

Estrogen receptor (ER) is a ligand-inducible hormone nuclear receptor that has important physiology and pathology roles in various human systems. My work focused on understanding the combinatorial complexity of ER, FOXA1 and GATA3 regulatory control on a genomic scale. We observe that these three transcription factors (TFs) form a functional enhanceosome that regulates the genes driving core ER function and cooperatively modulate the transcriptional networks previously ascribed to ER alone. We demonstrate that these enhanceosome occupied sites are associated with optimal enhancer characteristics with highest p300 coactivator 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-negative cells to restore the estrogen responsive growth resembling estrogen treated ER-positive cells. Cumulatively, these results suggest that all the enhanceosome components comprising ER, FOXA1 and GATA3 are necessary for the full repertoire of cancer associated effects of the ER.