TY - JOUR
T1 - Molecular subtype-specific expression of MicroRNA-29c in breast cancer is associated with CpG dinucleotide methylation of the promoter
AU - Poli, Elizabeth
AU - Zhang, Jing
AU - Nwachukwu, Chika
AU - Zheng, Yonglan
AU - Adedokun, Babatunde
AU - Olopade, Olufunmilayo I.
AU - Han, Yoo Jeong
N1 - Funding Information:
We thank Dr. Tatyana Grushko and Ms. Maria Gomez for assistance with FISH experiments and data interpretation, and Ms. Mariann Coyle for assistance with the cell culturing. This work was supported by funding to E. P. from Howard Hughes Medical Fellows Program, O.I.O. and Y.H from the Breast Cancer Research Foundation and the Ralph and Marion Falk Medical Research Trust. This research was also supported by the National Institute of Health-Specialized Program of Research Excellence in Breast Cancer (P50 CA125183 to OIO). OIO is American Cancer Society Clinical Research Professor.
Publisher Copyright:
© 2015 Poli et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/11/5
Y1 - 2015/11/5
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0142224
DO - 10.1371/journal.pone.0142224
M3 - Article
C2 - 26539832
AN - SCOPUS:84951325551
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 11
M1 - e0142224
ER -