The DNA binding sites of estrogen receptor α (ERbs) are key flexible genomic regions under hormone regulation. Tamoxifen is a widely applied therapy in breast cancer, affecting ER interactions and shifting their DNA-binding signature after prolonged exposure. Although tamoxifen inhibits the progression of breast cancer, it increases the risk of endometrial cancer. It has been shown that ER positioning in the endometrial cells of patients previously treated with tamoxifen resembles the signature of ER in mammary cancer cells. Our previous results showed that nearly 50% of ERbs of endometrial adenocarcinoma cells are shared by PR. This could explain part of the progestin regulation of estrogen effects on ER and PR-positive endometrial cancer cells. 
Here, we explore specific endometrial transcription factor cistromes, transcription and genomic structure of tamoxifen users, non-users, and of Ishikawa cells, a model of endometrial adenocarcinoma cells. We found that the ER cistrome of tamoxifen users is like Ishikawa ER cistrome, while ER cistrome of non-users is closer to transcriptionally active Ishikawa PR cistrome. ER binding signal in the subset of regions bounded by ER and not co-occupied by PR in Ishikawa cells was higher in tamoxifen users than in non-users. This correlated with their H3K27ac signal, indicating that tamoxifen could activate enhancer regions bounded by ER that could not be co-regulated by PR. These results indicate that tamoxifen treatment could change the ER chromatin landscape of endometrial tumor cells. The subset of ERbs of tamoxifen users that are shared by Ishikawa ERbs is enriched in early estrogen response pathway genes. On the other hand, the subset of ERbs of non-users shared by Ishikawa PRbs is enriched in NOTCH signaling pathway genes. These results propose a possible mechanism to explain a context-dependent response of genomic regions to be considered to prevent deregulation of endometrial cells under tamoxifen treatment.