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.
authors: Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors: Pei-Yin
authors: PY
authors: Hsu
authors: Daniel E
authors: DE
authors: Deatherage
authors: Benjamin A T
authors: BA
authors: Rodriguez
authors: Sandya
authors: S
authors: Liyanarachchi
authors: Yu-I
authors: YI
authors: Weng
authors: Tao
authors: T
authors: Zuo
authors: Joseph
authors: J
authors: Liu
authors: Alfred S L
authors: AS
authors: Cheng
authors: Tim H-M
authors: TH
authors: Huang
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001940:Breast / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D004054:Diethylstilbestrol / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D006877:Hydroxamic Acids; D035683:MicroRNAs; C012589:trichostatin A; D004054:Diethylstilbestrol; D000077209:Decitabine; D001374:Azacitidine