Estrogen receptor-α (ER) is the key feature of most breast cancers and binding 
of ER to the genome correlates with expression of the Forkhead protein FOXA1 
(also called HNF3α). Here we show that FOXA1 is a key determinant that can 
influence differential interactions between ER and chromatin. Almost all 
ER-chromatin interactions and gene expression changes depended on the presence 
of FOXA1 and FOXA1 influenced genome-wide chromatin accessibility. Furthermore, 
we found that CTCF was an upstream negative regulator of FOXA1-chromatin 
interactions. In estrogen-responsive breast cancer cells, the dependency on 
FOXA1 for tamoxifen-ER activity was absolute; in tamoxifen-resistant cells, ER 
binding was independent of ligand but depended on FOXA1. Expression of FOXA1 in 
non-breast cancer cells can alter ER binding and function. As such, FOXA1 is a 
major determinant of estrogen-ER activity and endocrine response in breast 
cancer cells.