Chromatin landscape of endometrial tumor cells of tamoxifen users is associated with loss of progestin regulation

Tamoxifen is an effective and widely steroid estrogen receptor modulator (SERM) used in the treatment of breast cancer applied therapy in breast cancer. It acts through competitive inhibition of natural ligand estrogen (E2) of 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. Tamoxifen could shift the DNA-binding signature of endometrial ERα upon prolonged exposure during breast cancer, resembling the signature of endometrial ERα in mammary cancer cells. Our laboratory had previously analyzed the progesterone receptor (PR) and ERα cistromes of endometrial adenocarcinoma Ishikawa cells when treated with ovarian hormones, showing that ERα binding sites are shared by PR in these endometrial adenocarcinoma cell line. This could explain, in part, progestin regulation of estrogen effects on ER/PR positive endometrial cancer cells. Here, we compared ERα cistromes of endometrial tumors of both tamoxifen users and non-users with the ERα and PR cistromes of the adenocarcinoma cell model. We found that ER cistrome of non-users is closer to transcriptionally active Ishikawa PR cistrome after R5020 treatment, while the ER cistrome of tamoxifen users is similar to Ishikawa ER cistrome after E2 treatment. These results indicate that tamoxifen treatment could change the ER chromatin landscape of endometrial tumor cells that can be occupied by PR in response to progestins. The subset of ERbs of non-users that could be shared by PR is enriched in NOTCH and inflammatory signaling pathway genes. On the other hand, the subset of ERbs of tamoxifen users that could be shared by ER in Ishikawa cells is enriched in early estrogen response pathway genes. These results could explain a context dependent response of genomic regions critical to be taken into account to prevent a deregulation of endometrial cells under tamoxifen treatment.