By optimizing the E2 deprivation and re-stimulation cell culture protocol that mimic the decrease of E2 levels in blood of breast cancer patients treated with aromatase inhibitors, a treatment that often evolves into an endocrine resistance after prolonged use (24), in conjunction with the latest methylation arrays, transcriptome (RNA-Seq) and chromatin (ChIP-Seq) analyses, we provide new insights into the genome-wide epigenetic dynamics of ligand-mediated ER activity in breast cancer cells. Here, ESR1 is linked to breast cancer.