Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ER alpha in Tamoxifen-Associated Endometrial Carcinomas

Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ER alpha) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ER alpha transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ER alpha-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ER alpha was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ER alpha binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ER alpha binding sites proximal to genes involved in classical ER alpha target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ER alpha and FOXA1 together with the enhance-renriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ER alpha expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ER alpha in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ER alpha are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. (C) 2016 AACR