The chromatin landscape of tamoxifen-associated endometrial tumors is reshaped toward estrogen receptor alpha sites independent of progesterone signaling

Abstract Tamoxifen is an effective steroid estrogen receptor modulator (SERM) widely used in breast cancer treatment. It acts through competitive inhibition of natural ligand estrogen (E2) at the estrogen receptor (ER), affecting ERα interactions with other nuclear receptors, chromatin modulators, genomic structural proteins and co-regulators. Although tamoxifen inhibits the progression of breast cancer, it increases the risk of endometrial cancer, particularly in postmenopausal women. Progesterone receptor (PR) and ERα cistromes of endometrial adenocarcinoma Ishikawa cells treated with ovarian hormones showed that ERα binding sites are shared by PR at open sites of chromatin. This could explain, in part, progestin regulation of estrogen effects on ER/PR positive endometrial cancer cells. Here, we compared ERα cistromes from endometrial tumors of tamoxifen users and non-users with ERα and PR cistromes from Ishikawal model to evaluate how SERM exposure affects ER-binding signature. Non-user ER cistrome is closer to R5020-treated Ishikawa PR cistrome, while tamoxifen users ER cistrome is similar to estradiol-treated Ishikawa ER cistrome. The subset of ERbs of non-users regulates inflammatory signaling pathway genes. In contrast, the subset of ERbs of tamoxifen users modulates early estrogen response pathway genes, such as the oncogene NRIP1. This suggests that exposure to tamoxifen redirects ERα binding toward genomic regions typically responsive to estrogen, whereas ERα binding in non-users retains features associated with PR-occupied regulatory sites. These results provide an example of how SERM treatment may remodel endometrial tumor epigenetic landscape, highlighting context-dependent genomic responses that should be considered to prevent deregulation of endometrial tissue under tamoxifen exposure. Competing Interest Statement The authors have declared no competing interest. Footnotes There has been slight changes to abstract and discussion sections.