The interplay between mitogenic and proinflammatory signaling pathways plays key roles in determining the phenotypes and clinical outcomes of breast cancers. Using GRO-seq in MCF-7 cells, we defined the immediate transcriptional effects of crosstalk between estradiol (E2) and TNFα, identifying a large set of target genes whose expression is rapidly altered with combined E2 + TNFα treatment, but not with either agent alone. The pleiotropic effects on gene transcription in response to E2 + TNFα are orchestrated by extensive remodeling of the ERα enhancer landscape in an NF-κB- and FoxA1-dependent manner. In addition, expression of the de novo and synergistically regulated genes is strongly associated with clinical outcomes in breast cancers. Together, our genomic and molecular analyses indicate that TNFα signaling, acting in pathways culminating in the redistribution of NF-κB and FoxA1 binding sites across the genome, creates latent ERα binding sites that underlie altered patterns of gene expression and clinically relevant cellular responses.