Comparative cistromic analysis reveals a shift in tamoxifen-associated endometrial tumor ERα binding toward sites less frequently shared by progesterone receptors

Tamoxifen, a selective estrogen receptor modulator (SERM) widely used in breast cancer treatment, paradoxically increases endometrial cancer risk. Although progesterone receptor (PR) shares estrogen receptor alpha (ERa) binding sites in Ishikawa endometrial adenocarcinoma cells, that could explain in part progestin regulation of estrogen effects, whether long term tamoxifen exposure alters this ERa/PR interplay in endometrial tumors remains unknown. Given the absence of endometrial tumor PR cistrome data, we compared ERa cistromes from tumors of users and non-users with Ishikawa cells ERa and PR cistromes to investigate how long-term SERM exposure might affect ERa binding signatures. Here, we show that non-user ERa binding exhibits greater similarity to the PR cistrome than tamoxifen users. These shared ERa-PR binding sites are not enriched in estrogen response elements (EREs) but in AP-1 and SOX motifs, suggesting indirect or tethered ERa recruitment, and are associated with genes involved in inflammatory pathways, such as MYC. In contrast, tamoxifen exposure appears to shift ERa binding toward PR-independent regions enriched in ERE motifs, and that could regulate early estrogen response pathways genes, including the oncogene NRIP1. Our findings suggest that exposure to tamoxifen may redirect ERa binding toward genomic regions responsive to estrogen, whereas ERa binding in non-users retains features associated with PR-occupied regulatory sites. These results provide bases for further investigation about the role that SERM treatment could play in remodeling the endometrial tumor epigenetic landscape and point to the hypothesis that this remodeling may involve altered ERa/PR regulatory interplay, potentially contributing to endometrial tissue dysregulation.