The mammary luminal lineage relies on the common cytokine-sensing transcription 
factor STAT5 to establish super-enhancers during pregnancy and initiate a 
genetic program that activates milk production. As pups grow, the greatly 
increasing demand for milk requires progressive differentiation of mammary cells 
with advancing lactation. Here we investigate how persistent hormonal exposure 
during lactation shapes an evolving enhancer landscape and impacts the biology 
of mammary cells. Employing ChIP-seq, we uncover a changing transcription factor 
occupancy at mammary enhancers, suggesting that their activities evolve with 
advancing differentiation. Using mouse genetics, we demonstrate that the 
functions of individual enhancers within the Wap super-enhancer evolve as 
lactation progresses. Most profoundly, a seed enhancer, which is mandatory for 
the activation of the Wap super-enhancer during pregnancy, is not required 
during lactation, suggesting compensatory flexibility. Combinatorial deletions 
of structurally equivalent constituent enhancers demonstrated 
differentiation-specific compensatory activities during lactation. We also 
demonstrate that the Wap super-enhancer, which is built on STAT5 and other 
common transcription factors, retains its exquisite mammary specificity when 
placed into globally permissive chromatin, suggesting a limited role of 
chromatin in controlling cell specificity. Our studies unveil a previously 
unrecognized progressive enhancer landscape where structurally equivalent 
components serve unique and differentiation-specific functions.