Epigenetic and transcriptome responsiveness to ER modulation by tissue selective estrogen complexes in breast epithelial and breast cancer cells.

Autor: Messier TL; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America.; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America., Boyd JR; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America., Gordon JAR; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America.; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America., Tye CE; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America.; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America., Page NA; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America., Toor RH; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America., Zaidi SK; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America.; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America., Komm BS; Komm Pharma Consulting LLC, San Francisco, CA, United States of America., Frietze S; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America.; Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, United States of America., Stein JL; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America.; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America., Lian JB; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America.; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America., Stein GS; Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America.; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America.; Department of Surgery, University of Vermont, Burlington, VT, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2022 Jul 21; Vol. 17 (7), pp. e0271725. Date of Electronic Publication: 2022 Jul 21 (Print Publication: 2022).
DOI: 10.1371/journal.pone.0271725
Abstrakt: Selective estrogen receptor modulators (SERMs), including the SERM/SERD bazedoxifene (BZA), are used to treat postmenopausal osteoporosis and may reduce breast cancer (BCa) risk. One of the most persistent unresolved questions regarding menopausal hormone therapy is compromised control of proliferation and phenotype because of short- or long-term administration of mixed-function estrogen receptor (ER) ligands. To gain insight into epigenetic effectors of the transcriptomes of hormone and BZA-treated BCa cells, we evaluated a panel of histone modifications. The impact of short-term hormone treatment and BZA on gene expression and genome-wide epigenetic profiles was examined in ERαneg mammary epithelial cells (MCF10A) and ERα+ luminal breast cancer cells (MCF7). We tested individual components and combinations of 17β-estradiol (E2), estrogen compounds (EC10) and BZA. RNA-seq for gene expression and ChIP-seq for active (H3K4me3, H3K4ac, H3K27ac) and repressive (H3K27me3) histone modifications were performed. Our results show that the combination of BZA with E2 or EC10 reduces estrogen-mediated patterns of histone modifications and gene expression in MCF-7ERα+ cells. In contrast, BZA has minimal effects on these parameters in MCF10A mammary epithelial cells. BZA-induced changes in histone modifications in MCF7 cells are characterized by altered H3K4ac patterns, with changes at distal enhancers of ERα-target genes and at promoters of non-ERα bound proliferation-related genes. Notably, the ERα target gene GREB1 is the most sensitive to BZA treatment. Our findings provide direct mechanistic-based evidence that BZA induces epigenetic changes in E2 and EC10 mediated control of ERα regulatory programs to target distinctive proliferation gene pathways that restrain the potential for breast cancer development.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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