Estrogen and progesterone are essential for mammary growth and differentiation, but also enhance the activity of the p53 tumor suppressor protein in the mammary epithelium. However, the pathways by which estrogen and progesterone regulate p53 activity are unknown. Microarrays were used to profile the transcriptional changes within the mammary gland following administration of either vehicle (V), 17-estradiol (E) or progesterone (P) individually and combined (EP). Treatment with EP yielded 1182 unique genes that were differentially expressed compared to the Vehicle-treated group. Although 30% of genes were responsive to either estrogen or progesterone individually, combined treatment with both EP had a synergistic effect accounting for 60% of the differentially regulated genes. Analysis of protein-protein interactions identified p53, RelA, Snw1 and Igfals as common targets of genes induced by EP. RelA and p53 form hubs within a network connected by genes that are regulated by EP and which may coordinate the competing functions of RelA and p53 in proliferation and survival of cells. Induction of early growth response 1 (Egr1) and Sfn (also known as 14–3-3) by EP was confirmed by RT-qPCR and was shown to be p53-independent. In luciferase reporter assays, Egr1 was shown to simultaneously enhance transcriptional activation via p53-responsive elements and inhibit NF-kB activity. These results identify a gene expression network that provides redundant activation of RelA to support proliferation as well as sensitize p53 to assure proper surveillance and integration of their competing functions through factors such as Egr1 which both enhance p53 and inhibit RelA.