A small set of accessible enhancers enables breast cancer cell response to physiological progestin concentrations

Here, we report that in T47D breast cancer cells 50pM progestin is sufficient to activate cell cycle entry and the progesterone gene expression program in breast cancer cells. At this concentration, equivalent to the progesterone blood levels found around the menopause, PR binds only to 2,800 genomic sites, which are accessible to ATAC cleavage prior to hormone. These Highly-Accessible PR Binding sites (HAPRBs) are surrounded by well-organized nucleosomes and exhibit breast enhancer features, including higher estrogen receptor (ERa), FOXA1 and BRD4 occupancy. Although, HAPRBs are enriched in RAD21 and CTCF, PR binding is the driving force for the most robust interactions with hormone-regulated genes. HAPRBs show higher frequency of 3D contacts among themselves than with other PRBs, indicating co-localization in similar compartment. Gene regulation  via  HAPRBs is independent of classical co-regulators and ATP-activated remodelers, relaying mainly on MAP kinase activation that enables PR nuclear engagement.  HAPRBs are also preferentially occupied by PR and ERa in breast cancer xenografts derived from MCF-7 cells as well as from patients (PDXs), indicating their usefulness as potential targets for therapeutic intervention. HiChIP, ChiP-seq, RNA-seq, ATAC-seq