The estrogen receptor- (ER) represents one of the most successful molecular entities as both a biomarker and target for cancer therapy, but some 30-50% of patients show de novo or acquired resistance. ER is a ligand regulated transcription factor that acts as a scaffold for histone modifying enzymes to modulate gene expression and growth of ER+ breast cancers (BCs). Importantly, the different treatment modalities of SERMs, SERDs and aromatase inhibitors induce different conformational effects on ER that often allow resistance to one type of treatment to be effectively treated by another. There is currently a significant unmet clinical need for new therapies that are effective in de novo and acquired resistance models, such as overexpression of receptor tyrosine kinases or activation of their downstream signaling pathways. We recently showed that an EGFR overexpression model rendered breast cancer cells broadly resistant to SERMs, as seen in patients. We also developed a new chemical targeting strategy for ER, which we call dual mechanism ER inhibitors (DMERI). Importantly, we identified both SERM and SERD DMERI as efficacious in the EGFR overexpression model, and many of them showed efficacy greater than fulvestrant, and in fulvestrant resistance models. The SERM DMERI may be an effective treatment for patients with EGFR overexpression at initial presentation, comprising a significant subset of ER+ BCs associated with clinical resistance. The marked difference in efficacy between SERMs and SERM DMERI in this resistant model provide us with robust chemical biology tools to dissect mechanisms of action. Our first goal is to understand the mechanisms of ER/EGFR signaling crosstalk and its regulation by different classes of ER ligands. A second goal is to understand the molecular mechanisms of ligand efficacy more generally through identifying ligand-specific coregulator- gene networks that regulate ER-dependent growth inhibition. The delineation of the ligand-receptor-coregulator gene code will enable understanding ligand mechanism of action and basic principles of transcription regulation in control of cell growth.