title: CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer.
abstract: Triple-negative breast cancer (TNBC) occurs in approximately 15% of all breast cancer patients, and the incidence of TNBC is greatly increased in BRCA1 mutation carriers. This study aimed to assess the impact of BRCA1 promoter methylation with respect to breast cancer subtypes in sporadic disease. Tissue microarrays (TMAs) were constructed representing tumors from 303 patients previously screened for BRCA1 germline mutations, of which a subset of 111 sporadic tumors had previously been analyzed with respect to BRCA1 methylation. Additionally, a set of eight tumors from BRCA1 mutation carriers were included on the TMAs. Expression analysis was performed on TMAs by immunohistochemistry (IHC) for BRCA1, pRb, p16, p53, PTEN, ER, PR, HER2, CK5/6, EGFR, MUC1 and Ki-67. Data on BRCA1 aberrations and IHC expression was examined with respect to breast cancer-specific survival. The results demonstrate that CpG island hypermethylation of BRCA1 significantly associates with the basal/triple-negative subtype. Low expression of pRb, and high/intense p16, were associated with BRCA1 promoter hypermethylation, and the same effects were seen in BRCA1 mutated tumors. The expression patterns of BRCA1, pRb, p16 and PTEN were highly correlated, and define a subgroup of TNBCs characterized by BRCA1 aberrations, high Ki-67 (≥ 40%) and favorable disease outcome. In conclusion, our findings demonstrate that epigenetic inactivation of the BRCA1 gene associates with RB/p16 dysfunction in promoting TNBCs. The clinical implications relate to the potential use of targeted treatment based on PARP inhibitors in sporadic TNBCs, wherein CpG island hypermethylation of BRCA1 represents a potential marker of therapeutic response.
authors: Cancer Research Laboratory, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Olafur Andri
authors: OA
authors: Stefansson
authors: Jon Gunnlaugur
authors: JG
authors: Jonasson
authors: Kristrun
authors: K
authors: Olafsdottir
authors: Holmfridur
authors: H
authors: Hilmarsdottir
authors: Gudridur
authors: G
authors: Olafsdottir
authors: Manel
authors: M
authors: Esteller
authors: Oskar Thor
authors: OT
authors: Johannsson
authors: Jorunn Erla
authors: JE
authors: Eyfjord
references: J Natl Cancer Inst. 2000 Apr 5;92(7):564-9
references: 10749912
references: Breast Cancer Res. 2009;11(4):R47
references: 19589159
references: Nat Med. 2009 Aug;15(8):907-13
references: 19648928
references: Clin Cancer Res. 2010 Oct 1;16(19):4702-10
references: 20858840
references: J Clin Oncol. 2010 Mar 1;28(7):1145-53
references: 20100965
references: Cancer Cell. 2007 Nov;12(5):479-91
references: 17996651
references: Science. 1994 Oct 7;266(5182):66-71
references: 7545954
references: Mol Oncol. 2011 Feb;5(1):5-23
references: 21147047
references: Am J Hum Genet. 1997 May;60(5):1079-84
references: 9150155
references: Oncogene. 2006 Sep 25;25(43):5864-74
references: 16998501
references: Breast Cancer Res Treat. 2005 May;91(2):179-86
references: 15868446
references: Clin Cancer Res. 2010 Sep 15;16(18):4517-26
references: 20823142
references: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23
references: 12829800
references: Nat Genet. 2008 Jan;40(1):102-7
references: 18066063
references: Clin Breast Cancer. 2009 Feb;9(1):29-33
references: 19299237
references: N Engl J Med. 2009 Jul 9;361(2):123-34
references: 19553641
references: J Natl Cancer Inst. 2006 Jan 18;98(2):116-22
references: 16418514
references: N Engl J Med. 2008 Mar 13;358(11):1148-59
references: 18337604
references: Cancer Res. 2006 Feb 15;66(4):2019-27
references: 16489001
references: Breast Cancer Res. 2010;12(5):R68
references: 20813035
references: Oncogene. 1999 Mar 18;18(11):1957-65
references: 10208417
references: Clin Cancer Res. 2004 Oct 1;10(19):6622-8
references: 15475452
references: Clin Cancer Res. 2005 Jul 15;11(14):5175-80
references: 16033833
references: Clin Cancer Res. 2004 Aug 15;10(16):5367-74
references: 15328174
references: J Natl Cancer Inst. 2009 May 20;101(10):736-50
references: 19436038
references: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13820-5
references: 19666588
references: Nat Genet. 1996 May;13(1):117-9
references: 8673089
references: Hum Pathol. 2008 Jun;39(6):857-65
references: 18400253
references: Hum Mutat. 1998;Suppl 1:S195-7
references: 9452084
references: N Engl J Med. 2010 Nov 11;363(20):1938-48
references: 21067385
references: Clin Cancer Res. 2008 Dec 15;14(24):8010-8
references: 19088017
references: N Engl J Med. 2011 Jan 20;364(3):205-14
references: 21208101
references: Breast Cancer Res. 2006;8(4):R38
references: 16846527
references: Cancer Cell. 2006 Feb;9(2):121-32
references: 16473279
references: Science. 1994 Oct 7;266(5182):120-2
references: 7939630
references: Cancer Res. 2005 Dec 1;65(23):10692-9
references: 16322213
references: Oncogene. 2008 May 15;27(22):3165-75
references: 18071313
references: Cancer Res. 2005 Feb 1;65(3):822-7
references: 15705879
references: Nat Rev Cancer. 2004 Oct;4(10):814-9
references: 15510162
references: J Biol Chem. 2010 Oct 22;285(43):33134-33143
references: 20713352
references: Oncogene. 2007 Mar 29;26(14):2126-32
references: 17016441
references: Cancer Res. 2009 Apr 15;69(8):3625-33
references: 19336573
references: J Natl Cancer Inst. 2003 Oct 1;95(19):1482-5
references: 14519755
references: Clin Cancer Res. 2008 Mar 1;14(5):1368-76
references: 18316557
references: J Clin Oncol. 2010 Oct 10;28(29):e563-4; author reply e565-6
references: 20679605
references: Breast Cancer Res. 2008;10(5):R75
references: 18782450