Although most ER-positive tumors initially respond to hormonal therapies such as tamoxifen, the effectiveness of these agents is limited by the development of resistance to tamoxifen induced growth inhibition.The mechanisms of resistance to hormone therapy, either inherent or acquired during treatment, remain poorly understood.One of the major challenges for hormone therapies of advanced breast cancer is to better understand the cellular basis of tamoxifen resistance and consequently develop novel approaches to overcoming endocrine resistance.The mechanisms underlining hormone resistance include ER activation in the absence of estrogen, hypersensitivity of ER to low levels of circulating estrogens, or ER activation, rather than inhibition, by estrogen antagonists.Emerging data suggest that the status and functionality of ER coregulatory proteins in nuclear and cytoplasm and cross-talking between ER coregulators and components of growth factors receptors play important roles in acquiring resistance to anti-estrogen action.We applied in vitro cell culture models and validated in a physiologically relevant whole-animal model to understand the functions and molecular events of ER coregulators in hormone resistance.Our data show that both genomic and nongenomic signaling pathways mediated by coregulators play prominent roles in resistance to tamoxifen.By understanding which of these pathways is involved in mediation of resistance, we might be able to develop strategies for overcoming or bypassing such resistance.