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Updated: Mar 21, 2026
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial
Marjolein Droog1, Ekaterina Nevedomskaya2, Yongsoo Kim2
1Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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.
Insights
Tamoxifen increases endometrial cancer risk. This study reveals conserved genomic interactions between estrogen receptor alpha (ERα) and FOXA1 in breast and endometrial cancers, explaining tamoxifen
Area of Science:
- Genomics
- Cancer Biology
- Endocrinology
Background:
- Tamoxifen, an estrogen receptor alpha (ERα) antagonist, treats breast cancer but elevates endometrial cancer risk.
- The underlying molecular mechanisms linking ERα activity in breast and endometrial tumors remain unclear.
Purpose of the Study:
- To investigate genome-wide ERα-chromatin interactions in tamoxifen-associated endometrial cancer.
- To identify conserved ERα binding sites and regulatory networks between breast and endometrial cancers.
Main Methods:
- Genome-wide assessment of ERα-chromatin interactions using ChIP-seq in patient surgical specimens.
- Analysis of ERα binding sites, histone modifications (H3K27Ac), and transcription factor motifs (FOXA1).
- Integration of multifactorial ChIP-seq data and immunohistochemical analysis of primary endometrial tumors.
Main Results:
- ERα binds to active enhancers in endometrial cancer cells, marked by RNA polymerase II and H3K27Ac.
- ERα binding sites are conserved between breast and endometrial cancers, enriched for FOXA1 motifs.
- A genomic network involving ERα, FOXA1, and other regulators (p300, FOXM1, TEAD4, etc.) was identified.
- Lack of FOXA1 and ERα expression correlated with a longer interval to endometrial cancer in tamoxifen-treated patients.
Conclusions:
- Defines conserved genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer.
- Suggests FOXA1 and ERα are key factors in the development of endometrial cancer following tamoxifen treatment.
