The cell-cell interactions that occur within the breast tumor microenvironment are critical determinants of cancer cell fate. In the face of treatment, the theory of clonal evolution dominates current thinking. Thus, individual cells may acquire a mutation(s) that provides a selection advantage, i.e., Darwinian selection acts at the single cell level. We studied the effect of antiestrogen treatment on the population remodeling of admixtures of sensitive (S) and resistant (R) human breast cancer cells. R cells were derived from S cells by selection against antiestrogens. We labeled S cells with GFP and R cells with mCherry, mixed the cells in different ratios, and treated with antiestrogen or vehicle. Unlike other resistance phenotypes, R cells do not out-compete S cells, nor do S cells restrain R cell growth. Rather, R cells protect S cells from treatment. Full communication of the resistance phenotype occurs at a 1:1 mixture of S:R; ˜75% of the R phenotype transfer is evident at 10:1. These results reflect improved fitness conferred by population interactions, not clonal evolution. SILAC analysis of S and R cells (pure populations) implicate differential regulation of E2 response-early; E2 response-late; glycolysis; fatty acid metabolism; mTORC1 signaling; peroxisome; UPR; oxidative phosphorylation in S vs. R cells. Clustering of iTRAQ-TAT data from pure and admixed S:R populations shows that the 1:1 and 5:1 treated, and the 1:1 untreated admixtures, cluster with pure R cells. Untreated 5:1 admixed cells cluster with untreated S cells. Thus, R and S cells alter each others molecular signatures. Studies using scratch labeling and small molecule inhibitors show that R cells communicate with S cells via both juxtacrine and paracrine interactions mediated by gap junctional intracellular communication and secreted microvesicles, respectively. The molecular features modified reflect our unifying hypothesis of signaling and cell function control in endocrine resistance.