Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas.

Abstract

Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα 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 ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERα 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 ERα binding sites proximal to genes involved in classical ERα target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERα and FOXA1 together with the enhancer-enriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERα 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 ERα in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERα are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773-84. ©2016 AACR.

• Authors: Marjolein Droog, Ekaterina Nevedomskaya, Yongsoo Kim, Tesa Severson, Koen D Flach, Mark Opdam, Karianne Schuurman, Patrycja Gradowska, Michael Hauptmann, Gwen Dackus, Harry Hollema, Marian Mourits, Petra Nederlof, Hester van Boven, Sabine C Linn, Lodewyk Wessels, Flora E van Leeuwen, Wilbert Zwart
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 13 Pg. 3773-84 (07 01 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27197147 (Publication Type: Comparative Study, Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Hormonal
• Biomarkers, Tumor
• ESR1 protein, human
• Estrogen Receptor alpha
• FOXA1 protein, human
• Hepatocyte Nuclear Factor 3-alpha
• RNA, Messenger
• Tamoxifen

Topics

• Antineoplastic Agents, Hormonal (therapeutic use)
• Biomarkers, Tumor (genetics)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Chromatin Immunoprecipitation
• Endometrial Neoplasms (drug therapy, genetics, metabolism, pathology)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Hepatocyte Nuclear Factor 3-alpha (genetics, metabolism)
• Humans
• Immunoenzyme Techniques
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Response Elements (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Tamoxifen (therapeutic use)