Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells.
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.
Hsu
Pei-Yin
PY
Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Deatherage
Daniel E
DE
Rodriguez
Benjamin A T
BA
Liyanarachchi
Sandya
S
Weng
Yu-I
YI
Zuo
Tao
T
Liu
Joseph
J
Cheng
Alfred S L
AS
Huang
Tim H-M
TH
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
D006877:Hydroxamic Acids; D035683:MicroRNAs; C012589:trichostatin A; D004054:Diethylstilbestrol; D000077209:Decitabine; D001374:Azacitidine