title: Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer.
abstract: Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes. Deciphering the molecular mechanisms that fuel breast cancer development and act as determinants of aggressiveness is a primary need to improve patient management. Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level. In this study, we describe a new role for miR-181a/b as negative regulators of the DNA damage response in breast cancer, impacting on the expression and activity of the stress-sensor kinase ataxia telangiectasia mutated (ATM). We report that miR-181a and miR-181b were overexpressed in more aggressive breast cancers, and their expression correlates inversely with ATM levels. Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple-negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition. These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types.
authors: Laboratorio Nazionale CIB, AREA Science Park, Trieste, Italy.
authors: Andrea
authors: A
authors: Bisso
authors: Michela
authors: M
authors: Faleschini
authors: Federico
authors: F
authors: Zampa
authors: Valeria
authors: V
authors: Capaci
authors: Jacopo
authors: J
authors: De Santa
authors: Libero
authors: L
authors: Santarpia
authors: Silvano
authors: S
authors: Piazza
authors: Vera
authors: V
authors: Cappelletti
authors: Mariagrazia
authors: M
authors: Daidone
authors: Reuven
authors: R
authors: Agami
authors: Giannino
authors: G
authors: Del Sal
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D004260:DNA Repair; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014162:Transfection
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D011065:Poly(ADP-ribose) Polymerases; D064007:Ataxia Telangiectasia Mutated Proteins; D051135:Rad51 Recombinase
keywords: ATM; BRCA1; BRCAness; DNA damage response; PARP inhibitors; breast cancer; microRNA
references: Cell. 2011 Oct 14;147(2):382-95
references: 22000016
references: Oncogene. 2011 Mar 24;30(12):1470-80
references: 21102523
references: PLoS One. 2011;6(6):e20980
references: 21738599
references: Nat Rev Clin Oncol. 2010 Dec;7(12):702-7
references: 20956982
references: PLoS One. 2011;6(8):e23271
references: 21876743
references: Mol Cell Biol. 2009 May;29(10):2841-51
references: 19273599
references: Cancer Res. 2010 Mar 1;70(5):1793-803
references: 20145152
references: Cell. 2009 Jan 23;136(2):215-33
references: 19167326
references: Nat Rev Mol Cell Biol. 2009 Feb;10(2):141-8
references: 19145236
references: Breast Cancer Res. 2003;5(1):45-52
references: 12559046
references: J Natl Cancer Inst. 2000 Apr 5;92(7):564-9
references: 10749912
references: Mol Cell. 2011 Jan 21;41(2):210-20
references: 21195000
references: Oncogene. 2006 Sep 25;25(43):5906-11
references: 16998505
references: J Clin Invest. 2013 Jan;123(1):150-63
references: 23241956
references: Cell Biosci. 2011 Jan 18;1(1):4
references: 21711587
references: Nature. 2012 Jan 18;481(7381):287-94
references: 22258607
references: Nat Rev Drug Discov. 2010 Oct;9(10):775-89
references: 20885409
references: Nature. 2006 Nov 30;444(7119):638-42
references: 17136094
references: Cell. 2007 Dec 14;131(6):1109-23
references: 18083101
references: Cancer Genomics Proteomics. 2006 Oct;3(5):317-324
references: 18172508
references: Nat Rev Mol Cell Biol. 2010 Mar;11(3):220-8
references: 20177397
references: EMBO Mol Med. 2011 May;3(5):279-90
references: 21472990
references: Carcinogenesis. 2012 Nov;33(11):2007-17
references: 22822097
references: Nature. 2005 Apr 14;434(7035):917-21
references: 15829967
references: Mol Cell Biol. 2003 Apr;23(7):2225-38
references: 12640109
references: Nat Rev Cancer. 2012 Sep;12(9):587-98
references: 22918414
references: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
references: 16461460
references: Nature. 2005 Apr 14;434(7035):864-70
references: 15829956
references: RNA. 2008 Nov;14(11):2348-60
references: 18812439
references: Nat Rev Cancer. 2011 Nov 24;11(12):849-64
references: 22113163
references: Mol Cell Biol. 2007 Mar;27(5):1859-67
references: 17194750
references: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1506-11
references: 20080624
references: Nat Biotechnol. 2011 May;29(5):373-4
references: 21552220
references: J Clin Oncol. 2010 Mar 1;28(7):1145-53
references: 20100965
references: EMBO Mol Med. 2012 Nov;4(11):1214-29
references: 23125021
references: Oncogene. 2010 Mar 25;29(12):1787-97
references: 20023698
references: Nature. 2012 Apr 04;486(7403):395-9
references: 22495314
references: Mol Cell. 2010 Aug 27;39(4):493-506
references: 20797623
references: Oncogene. 2008 Apr 10;27(17):2501-6
references: 17982490
references: Nat Rev Cancer. 2004 Oct;4(10):814-9
references: 15510162
references: Genes Cancer. 2010 Mar;1(3):210-24
references: 21779448
references: Nat Rev Cancer. 2011 Dec 23;12(1):68-78
references: 22193408
references: Nat Rev Genet. 2009 Oct;10(10):704-14
references: 19763153
references: Nat Rev Mol Cell Biol. 2008 Oct;9(10):759-69
references: 18813293
references: Clin Cancer Res. 2012 Apr 15;18(8):2344-51
references: 22371451
references: PLoS One. 2011;6(9):e25454
references: 21980462
references: Cell. 2010 Jun 25;141(7):1195-207
references: 20603000
references: Science. 1999 Nov 5;286(5442):1162-6
references: 10550055
references: J Clin Oncol. 2008 Mar 10;26(8):1275-81
references: 18250347