Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells

Pei Yin Hsu, Daniel E. Deatherage, Benjamin A T Rodriguez, Sandya Liyanarachchi, Yu I. Weng, Tao Zuo, Joseph Liu, Alfred S L Cheng, Hui-ming Huang

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

Early exposure to xenoestrogens may predispose to breast cancer risk later in adult life. It is likely that long-lived, self-regenerating epithelial progenitor cells are more susceptible to these exposure injuries over time and transmit the injured memory through epigenetic mechanisms to their differentiated progeny. Here, we used progenitor-containing mammospheres as an in vitro exposure model to study this epigenetic effect. Expression profiling identified that, relative to control cells, 9.1% of microRNAs (82 of 898 loci) were altered in epithelial progeny derived from mammospheres exposed to a synthetic estrogen, diethylstilbestrol. Repressive chromatin marks, trimethyl Lys27 of histone H3 (H3K27me3) and dimethyl Lys9 of histone H3 (H3K9me2), were found at a down-regulated locus, miR-9-3, in epithelial cells preexposed to diethylstilbestrol. This was accompanied by recruitment of DNA methyltransferase 1 that caused an aberrant increase in DNA methylation of its promoter CpG island in mammosphere-derived epithelial cells on diethylstilbestrol preexposure. Functional analyses suggest that miR-9-3 plays a role in the p53-related apoptotic pathway. Epigenetic silencing of this gene, therefore, reduces this cellular function and promotes the proliferation of breast cancer cells. Promoter hypermethylation of this microRNA may be a hallmark for early breast cancer development, and restoration of its expression by epigenetic and microRNA-based therapies is another viable option for future treatment of this disease.

Original languageEnglish (US)
Pages (from-to)5936-5945
Number of pages10
JournalCancer Research
Volume69
Issue number14
DOIs
StatePublished - Jul 15 2009
Externally publishedYes

Fingerprint

Epigenetic Repression
MicroRNAs
Epigenomics
Diethylstilbestrol
Breast
Epithelial Cells
Breast Neoplasms
Histones
Estradiol Congeners
CpG Islands
Methyltransferases
Gene Silencing
DNA Methylation
Chromatin
Stem Cells
DNA
Wounds and Injuries

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hsu, P. Y., Deatherage, D. E., Rodriguez, B. A. T., Liyanarachchi, S., Weng, Y. I., Zuo, T., ... Huang, H. (2009). Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. Cancer Research, 69(14), 5936-5945. https://doi.org/10.1158/0008-5472.CAN-08-4914

Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. / Hsu, Pei Yin; Deatherage, Daniel E.; Rodriguez, Benjamin A T; Liyanarachchi, Sandya; Weng, Yu I.; Zuo, Tao; Liu, Joseph; Cheng, Alfred S L; Huang, Hui-ming.

In: Cancer Research, Vol. 69, No. 14, 15.07.2009, p. 5936-5945.

Research output: Contribution to journalArticle

Hsu, PY, Deatherage, DE, Rodriguez, BAT, Liyanarachchi, S, Weng, YI, Zuo, T, Liu, J, Cheng, ASL & Huang, H 2009, 'Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells', Cancer Research, vol. 69, no. 14, pp. 5936-5945. https://doi.org/10.1158/0008-5472.CAN-08-4914
Hsu PY, Deatherage DE, Rodriguez BAT, Liyanarachchi S, Weng YI, Zuo T et al. Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. Cancer Research. 2009 Jul 15;69(14):5936-5945. https://doi.org/10.1158/0008-5472.CAN-08-4914
Hsu, Pei Yin ; Deatherage, Daniel E. ; Rodriguez, Benjamin A T ; Liyanarachchi, Sandya ; Weng, Yu I. ; Zuo, Tao ; Liu, Joseph ; Cheng, Alfred S L ; Huang, Hui-ming. / Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. In: Cancer Research. 2009 ; Vol. 69, No. 14. pp. 5936-5945.
@article{acf1b506077f40179dc149da36cf1c8c,
title = "Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells",
abstract = "Early exposure to xenoestrogens may predispose to breast cancer risk later in adult life. It is likely that long-lived, self-regenerating epithelial progenitor cells are more susceptible to these exposure injuries over time and transmit the injured memory through epigenetic mechanisms to their differentiated progeny. Here, we used progenitor-containing mammospheres as an in vitro exposure model to study this epigenetic effect. Expression profiling identified that, relative to control cells, 9.1{\%} of microRNAs (82 of 898 loci) were altered in epithelial progeny derived from mammospheres exposed to a synthetic estrogen, diethylstilbestrol. Repressive chromatin marks, trimethyl Lys27 of histone H3 (H3K27me3) and dimethyl Lys9 of histone H3 (H3K9me2), were found at a down-regulated locus, miR-9-3, in epithelial cells preexposed to diethylstilbestrol. This was accompanied by recruitment of DNA methyltransferase 1 that caused an aberrant increase in DNA methylation of its promoter CpG island in mammosphere-derived epithelial cells on diethylstilbestrol preexposure. Functional analyses suggest that miR-9-3 plays a role in the p53-related apoptotic pathway. Epigenetic silencing of this gene, therefore, reduces this cellular function and promotes the proliferation of breast cancer cells. Promoter hypermethylation of this microRNA may be a hallmark for early breast cancer development, and restoration of its expression by epigenetic and microRNA-based therapies is another viable option for future treatment of this disease.",
author = "Hsu, {Pei Yin} and Deatherage, {Daniel E.} and Rodriguez, {Benjamin A T} and Sandya Liyanarachchi and Weng, {Yu I.} and Tao Zuo and Joseph Liu and Cheng, {Alfred S L} and Hui-ming Huang",
year = "2009",
month = "7",
day = "15",
doi = "10.1158/0008-5472.CAN-08-4914",
language = "English (US)",
volume = "69",
pages = "5936--5945",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

TY - JOUR

T1 - Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells

AU - Hsu, Pei Yin

AU - Deatherage, Daniel E.

AU - Rodriguez, Benjamin A T

AU - Liyanarachchi, Sandya

AU - Weng, Yu I.

AU - Zuo, Tao

AU - Liu, Joseph

AU - Cheng, Alfred S L

AU - Huang, Hui-ming

PY - 2009/7/15

Y1 - 2009/7/15

N2 - Early exposure to xenoestrogens may predispose to breast cancer risk later in adult life. It is likely that long-lived, self-regenerating epithelial progenitor cells are more susceptible to these exposure injuries over time and transmit the injured memory through epigenetic mechanisms to their differentiated progeny. Here, we used progenitor-containing mammospheres as an in vitro exposure model to study this epigenetic effect. Expression profiling identified that, relative to control cells, 9.1% of microRNAs (82 of 898 loci) were altered in epithelial progeny derived from mammospheres exposed to a synthetic estrogen, diethylstilbestrol. Repressive chromatin marks, trimethyl Lys27 of histone H3 (H3K27me3) and dimethyl Lys9 of histone H3 (H3K9me2), were found at a down-regulated locus, miR-9-3, in epithelial cells preexposed to diethylstilbestrol. This was accompanied by recruitment of DNA methyltransferase 1 that caused an aberrant increase in DNA methylation of its promoter CpG island in mammosphere-derived epithelial cells on diethylstilbestrol preexposure. Functional analyses suggest that miR-9-3 plays a role in the p53-related apoptotic pathway. Epigenetic silencing of this gene, therefore, reduces this cellular function and promotes the proliferation of breast cancer cells. Promoter hypermethylation of this microRNA may be a hallmark for early breast cancer development, and restoration of its expression by epigenetic and microRNA-based therapies is another viable option for future treatment of this disease.

AB - Early exposure to xenoestrogens may predispose to breast cancer risk later in adult life. It is likely that long-lived, self-regenerating epithelial progenitor cells are more susceptible to these exposure injuries over time and transmit the injured memory through epigenetic mechanisms to their differentiated progeny. Here, we used progenitor-containing mammospheres as an in vitro exposure model to study this epigenetic effect. Expression profiling identified that, relative to control cells, 9.1% of microRNAs (82 of 898 loci) were altered in epithelial progeny derived from mammospheres exposed to a synthetic estrogen, diethylstilbestrol. Repressive chromatin marks, trimethyl Lys27 of histone H3 (H3K27me3) and dimethyl Lys9 of histone H3 (H3K9me2), were found at a down-regulated locus, miR-9-3, in epithelial cells preexposed to diethylstilbestrol. This was accompanied by recruitment of DNA methyltransferase 1 that caused an aberrant increase in DNA methylation of its promoter CpG island in mammosphere-derived epithelial cells on diethylstilbestrol preexposure. Functional analyses suggest that miR-9-3 plays a role in the p53-related apoptotic pathway. Epigenetic silencing of this gene, therefore, reduces this cellular function and promotes the proliferation of breast cancer cells. Promoter hypermethylation of this microRNA may be a hallmark for early breast cancer development, and restoration of its expression by epigenetic and microRNA-based therapies is another viable option for future treatment of this disease.

UR - http://www.scopus.com/inward/record.url?scp=67651006246&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651006246&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-08-4914

DO - 10.1158/0008-5472.CAN-08-4914

M3 - Article

C2 - 19549897

AN - SCOPUS:67651006246

VL - 69

SP - 5936

EP - 5945

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 14

ER -