Abstract In this R01 proposal, we plan to use an integrative genomics (Omics) analysis to test two central hypotheses: 1) an environmental or cellular stimulus such as hormones induced distinct chromatin interacting foci such as enhancer-enhancer looping foci play key roles in regulating cell transformed phenotype; and 2) 3D chromatin structures play key roles in governing cell identities. The ultimate goal is to dissect the relationship between chromatin interactions and cell identities or cellular phenotypes. Using a model system of ERα in breast cancer, we will a) identify distinct types of ERα-regulated chromatin interacting foci including promoter- enhancer, enhancer-enhancer and enhancer-repressor looping foci; and b) identify 3D-regulated breast cancer cell identities and sensitive-resistant transition cell subpopulations. The successful completion of our proposed studies will be of value to the genomics community and biologists in general, which may result in the better understanding of the contribution of enhancer-enhancer interacting network towards functions of various biological processes, in particular breast cancer endocrine resistance, and on how 3D chromatin structure governs the breast cancer sensitive cell subpopulations into resistant cell subpopulations.