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, Tim H.M. Huang

Research output: Contribution to journalArticle

105 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hsu, P. Y., Deatherage, D. E., Rodriguez, B. A. T., Liyanarachchi, S., Weng, Y. I., Zuo, T., Liu, J., Cheng, A. S. L., & Huang, T. H. M. (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