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

Epigenetic silencing of microRNA gene, miR-9-3, promotes the proliferation of breast cancer cells

2009 Study 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.

In conclusion, we have identified a microRNA gene, miR-9-3, which is frequently hypermethylated in breast cancer. One potential causal factor leading to this epigenetic repression is the prolonged exposure of breast progenitor cells to xenoestrogens. In our example, diethylstilbestrol acts as an estrogenic ligand that activates either genomic or nongenomic pathways to mediate gene transcription through down-regulation of the target microRNA, miR-9-3. Persistent activation of this signaling activity may further establish a repressive heterochromatin environment in the promoter CpG island region of this microRNA. Accumulation of DNA methylation later occurs in the region and leaves the heritable hallmark in differentiated progeny. Because miR-9-3 plays a role in regulating apoptosis, epigenetic silencing of this gene may promote proliferation of cancer cells. Restoration of its expression by the combined epigenetic and microRNA-based therapies, therefore, could be an additional approach for future treatment of breast cancer.

Sources and more information
  • Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells, Cancer research, NCBI PubMed PMC2855843, 2009 Jun 23.
  • Preexposure of MDECs to diethylstilbestrol and immunofluorescence analysis of nuclear ER-α. A, treatment scheme featured image credit PMC2855843/figure/F1.

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