In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2022-7-21), p. e0271725-
Kurzfassung:
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 ERα neg 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-7 ERα+ 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.
Materialart:
Online-Ressource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0271725
DOI:
10.1371/journal.pone.0271725.g001
DOI:
10.1371/journal.pone.0271725.g002
DOI:
10.1371/journal.pone.0271725.g003
DOI:
10.1371/journal.pone.0271725.g004
DOI:
10.1371/journal.pone.0271725.g005
DOI:
10.1371/journal.pone.0271725.s001
DOI:
10.1371/journal.pone.0271725.s002
DOI:
10.1371/journal.pone.0271725.s003
DOI:
10.1371/journal.pone.0271725.s004
DOI:
10.1371/journal.pone.0271725.s005
DOI:
10.1371/journal.pone.0271725.s006
DOI:
10.1371/journal.pone.0271725.s007
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2022
ZDB Id:
2267670-3
