title: Restoration of the methylation status of hypermethylated gene promoters by microRNA-29b in human breast cancer: A novel epigenetic therapeutic approach.
abstract: It is well established that transcriptional silencing of critical tumor-suppressor genes by DNA methylation is a fundamental component in the initiation of breast cancer. However, the involvement of microRNAs (miRNAs) in restoring abnormal DNA methylation patterns in breast cancer is not well understood. Therefore, we investigated whether miRNA-29b, due to its complimentarity to the 3'- untranslated region of DNA methyltransferase 3A (DNMT3A) and DNMT3B, could restore normal DNA methylation patterns in human breast cancers and breast cancer cell lines. We demonstrated that transfection of pre-miRNA-29b into less aggressive MCF-7 cells, but not MDA-MB-231 mesenchymal cells, inhibited cell proliferation, decreased DNMT3A and DNMT3B messenger RNA (mRNA), and decreased promoter methylation status of ADAM23 , CCNA1, CCND2, CDH1, CDKN1C, CDKN2A, HIC1, RASSF1, SLIT2, TNFRSF10D, and TP73 tumor-suppressor genes. Using methylation polymerase chain reaction (PCR) arrays and real-time PCR, we also demonstrated that the methylation status of several critical tumor-suppressor genes increased as stage of breast disease increased, while miRNA-29b mRNA levels were significantly decreased in breast cancers versus normal breast. This increase in methylation status was accompanied by an increase in DNMT1 and DNMT3B mRNA in advanced stage of human breast cancers and in MCF-7, MDA-MB-361, HCC70, Hs-578T, and MDA-MB-231 breast cancer cells as compared to normal breast specimens and MCF-10-2A, a non-tumorigenic breast cell line, respectively. Our findings highlight the potential for a new epigenetic approach in improving breast cancer therapy by targeting DNMT3A and DNMT3B through miRNA-29b in non-invasive epithelial breast cancer cells.
authors: Office of the Associate Director for Regulatory Activities, Jefferson, AR 72079, USA.
authors: Athena
authors: A
authors: Starlard-Davenport
authors: Kristi
authors: K
authors: Kutanzi
authors: Volodymyr
authors: V
authors: Tryndyak
authors: Beverly
authors: B
authors: Word
authors: Beverly
authors: B
authors: Lyn-Cook
keywords: Breast cancer; DNA methylation; DNA methyltransferase1; DNA methyltransferases 3A; DNA methyltransferases 3B; microRNA-29b
references: Recent Results Cancer Res. 2010;184:131-57
references: 20072836
references: Semin Oncol. 2005 Oct;32(5):443-51
references: 16210084
references: Curr Opin Oncol. 2005 Jan;17(1):55-60
references: 15608514
references: Cancer Biomark. 2010;9(1-6):41-64
references: 22112469
references: Cell. 2007 Feb 23;128(4):683-92
references: 17320506
references: Cell. 2009 Jun 12;137(6):1005-17
references: 19524505
references: J Mammary Gland Biol Neoplasia. 2010 Mar;15(1):19-33
references: 20131086
references: Cancer Res. 2007 Nov 15;67(22):11001-11
references: 18006846
references: Eur J Cancer. 2000 Dec;36(18):2294-300
references: 11094302
references: Semin Oncol. 2005 Oct;32(5):437-42
references: 16210083
references: Semin Cancer Biol. 2009 Jun;19(3):165-71
references: 19429480
references: FEBS Lett. 1999 Oct 29;460(2):231-4
references: 10544241
references: J Pathol. 2010 Jan;220(2):231-43
references: 19918804
references: Acta Clin Belg. 2011 Jul-Aug;66(4):283-92
references: 21938984
references: Biochim Biophys Acta. 2007 Jun;1770(6):847-56
references: 17368950
references: J Clin Invest. 2007 Nov;117(11):3155-63
references: 17975657
references: Future Oncol. 2009 Oct;5(8):1245-56
references: 19852739
references: Eur J Cancer. 2009 May;45(7):1129-1136
references: 19211243
references: Cancer Causes Control. 2009 Nov;20(9):1539-50
references: 19768562
references: Nat Protoc. 2008;3(6):1101-8
references: 18546601
references: Ann Oncol. 2011 Jan;22(1):24-29
references: 20591821
references: J Biol Chem. 2005 May 6;280(18):18302-10
references: 15755728
references: Clin Chem. 2011 Aug;57(8):1169-77
references: 21700955
references: RNA. 2009 Aug;15(8):1507-14
references: 19509302
references: Clin Cancer Res. 2003 Oct 1;9(12):4415-22
references: 14555514
references: Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15805-10
references: 17890317
references: Drugs Today (Barc). 2007 Jun;43(6):395-422
references: 17612710
references: Mutat Res. 2008 Dec 1;647(1-2):44-51
references: 18691602
references: J Mol Med (Berl). 2008 Dec;86(12):1315-28
references: 18716754
references: Eur J Pharmacol. 2009 Dec 25;625(1-3):131-42
references: 19836388
references: CA Cancer J Clin. 2011 Nov-Dec;61(6):409-18
references: 21969133
references: Mol Cancer. 2008 Jan 25;7:15
references: 18221536
references: Curr Med Chem. 2009;16(17):2075-85
references: 19519382
references: Blood. 2009 Jun 18;113(25):6411-8
references: 19211935
references: J Mammary Gland Biol Neoplasia. 2010 Mar;15(1):5-17
references: 20101446
references: Oncogene. 2009 Aug 20;28(33):2969-78
references: 19503099
references: Mol Oncol. 2010 Jun;4(3):242-54
references: 20627830
references: Clin Cancer Res. 2009 Jun 15;15(12):3938-46
references: 19509174