Abstract
Basal-like breast cancer is a molecularly distinct subtype of breast cancer that is highly aggressive and has a poor prognosis. MicroRNA-29c (miR-29c) has been shown to be significantly down-regulated in basal-like breast tumors and to be involved in cell invasion and sensitivity to chemotherapy. However, little is known about the genetic and regulatory factors contributing to the altered expression of miR-29c in basal-like breast cancer. We here report that epigenetic modifications at the miR-29c promoter, rather than copy number variation of the gene, may drive the lower expression of miR-29c in basal-like breast cancer. Bisulfite sequencing of CpG sites in the miR-29c promoter region showed higher methylation in basal-like breast cancer cell lines compared to luminal subtype cells with a significant inverse correlation between expression and methylation of miR-29c. Analysis of primary breast tumors using The Cancer Genome Atlas (TCGA) dataset confirmed significantly higher levels of methylation of the promoter in basal-like breast tumors compared to all other subtypes. Furthermore, inhibition of CpG methylation with 5-aza-CdR increases miR-29c expression in basal-like breast cancer cells. Flourescent In Situ Hybridization (FISH) revealed chromosomal abnormalities at miR-29c loci in breast cancer cell lines, but with no correlation between copy number variation and expression of miR-29c. Our data demonstrated that dysregulation of miR-29c in basal-like breast cancer cells may be in part driven by methylation at CpG sites. Epigenetic control of the miR-29c promoter by epigenetic modifiers may provide a potential therapeutic target to overcome the aggressive behavior of these cancers.
Highlights
Breast cancer affects more than 230,000 women, and results in nearly 40,000 deaths, making it the second deadliest cancer in women behind lung cancer [1]
To characterize expression of miR-29c in breast cancer subtypes and verify previous studies that have shown that miR-29c is expressed lower in the basal-like breast cancer subtype [12], we examined expression of the microRNA in breast cancer cell lines using qRT-PCR
We have identified the promoter of miR-29b2/29c to be 20kb upstream of the gene on Chromosome 1
Summary
Breast cancer affects more than 230,000 women, and results in nearly 40,000 deaths, making it the second deadliest cancer in women behind lung cancer [1]. MiR-29c has been shown to be downregulated in several cancers, such as gastric, peripheral nerve sheath tumors, esophageal squamous cell carcinoma, melanoma, and breast cancer, among others [12, 21, 22, 23] In these diseases, the decreased expression of miR-29c leads to the dysregulation of its downstream targets that are involved in epigenetic modification, metastasis, and cell proliferation, such as DNMT, B7-H3, RCC2, and cyclin E [12, 22, 24, 25, 26]. These results suggest that epigenetic changes may affect for the difference in expression of miR-29c in basal and luminal breast cancers, suggesting potential for regulation of miR-29c expression by epigenetic modifiers to be used as a therapeutic target for BLBC
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