title: BRCA1 pathway function in basal-like breast cancer cells.
abstract: Sporadic basal-like cancers (BLCs) are a common subtype of breast cancer that share multiple biological properties with BRCA1-mutated breast tumors. Despite being BRCA1(+/+), sporadic BLCs are widely viewed as phenocopies of BRCA1-mutated breast cancers, because they are hypothesized to manifest a BRCA1 functional defect or breakdown of a pathway(s) in which BRCA1 plays a major role. The role of BRCA1 in the repair of double-strand DNA breaks by homologous recombination (HR) is its best understood function and the function most often implicated in BRCA1 breast cancer suppression. Therefore, it is suspected that sporadic BLCs exhibit a defect in HR. To test this hypothesis, multiple DNA damage repair assays focused on several types of repair were performed on a group of cell lines classified as sporadic BLCs and on controls. The sporadic BLC cell lines failed to exhibit an overt HR defect. Rather, they exhibited defects in the repair of stalled replication forks, another BRCA1 function. These results provide insight into why clinical trials of poly(ADP-ribose) polymerase (PARP) inhibitors, which require an HR defect for efficacy, have been unsuccessful in sporadic BLCs, unlike cisplatin, which elicits DNA damage that requires stalled fork repair and has shown efficacy in sporadic BLCs.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hill
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Allison P
authors.initials: AP
authors.lastname: Clark
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Silver
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA david_livingston@dfci.harvard.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D018295:Neoplasms, Basal Cell; D059767:Recombinational DNA Repair
chemical_list: D019313:BRCA1 Protein; D009153:Mutagens; D008741:Methyl Methanesulfonate
references.citation: Nat Cell Biol. 2004 Oct;6(10):954-67
references.pmid: 15448696
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23
references.pmid: 12829800
references.citation: Nature. 2002 Jan 31;415(6871):530-6
references.pmid: 11823860
references.citation: Mol Cell. 2001 Feb;7(2):249-62
references.pmid: 11239454
references.citation: Genes Dev. 1999 Oct 15;13(20):2633-8
references.pmid: 10541549
references.citation: Cell. 2010 Apr 16;141(2):243-54
references.pmid: 20362325
references.citation: Mol Cancer Res. 2009 Aug;7(8):1304-9
references.pmid: 19671671
references.citation: Cell. 2006 Nov 3;127(3):539-52
references.pmid: 17081976
references.citation: Mol Cell. 2001 Jul;8(1):213-24
references.pmid: 11511374
references.citation: Nat Genet. 2001 Jul;28(3):266-71
references.pmid: 11431698
references.citation: Cell. 1997 Aug 8;90(3):425-35
references.pmid: 9267023
references.citation: Cancer Res. 2012 Nov 1;72(21):5588-99
references.pmid: 23118055
references.citation: Mol Oncol. 2011 Aug;5(4):387-93
references.pmid: 21821475
references.citation: Breast Cancer Res Treat. 2013 Apr;138(3):783-94
references.pmid: 23542956
references.citation: EMBO Rep. 2001 Nov;2(11):1013-7
references.pmid: 11713193
references.citation: EMBO Mol Med. 2011 May;3(5):279-90
references.pmid: 21472990
references.citation: Cell Cycle. 2012 Oct 15;11(20):3837-50
references.pmid: 22983061
references.citation: Nature. 2005 Apr 14;434(7035):917-21
references.pmid: 15829967
references.citation: N Engl J Med. 2009 Jul 9;361(2):123-34
references.pmid: 19553641
references.citation: Breast Cancer Res Treat. 2012 Jul;134(1):21-30
references.pmid: 22234518
references.citation: Ann Oncol. 2008 Nov;19(11):1847-52
references.pmid: 18567607
references.citation: Oncogene. 1998 Oct 1;17(13):1681-9
references.pmid: 9796697
references.citation: Mol Cell. 1999 Mar;3(3):389-95
references.pmid: 10198641
references.citation: Nature. 2000 Aug 17;406(6797):747-52
references.pmid: 10963602
references.citation: Cancer Res. 2009 Jan 15;69(2):663-71
references.pmid: 19147582
references.citation: Clin Cancer Res. 2005 Jul 15;11(14):5175-80
references.pmid: 16033833
references.citation: Mol Cell Biol. 2003 Nov;23(21):7926-36
references.pmid: 14560035
references.citation: Lancet Oncol. 2011 Sep;12(9):852-61
references.pmid: 21862407
references.citation: Br J Cancer. 2004 Jul 19;91(2):355-8
references.pmid: 15188009
references.citation: Cell. 2006 Nov 3;127(3):481-93
references.pmid: 17081972
references.citation: Nature. 2011 Sep 07;477(7363):179-84
references.pmid: 21901007
references.citation: Cancer Res. 2009 Apr 15;69(8):3589-96
references.pmid: 19351835
references.citation: Cancer Res. 2001 Nov 1;61(21):7713-8
references.pmid: 11691781
references.citation: Mol Cell. 2003 Jul;12(1):247-54
references.pmid: 12887909
references.citation: Cancer Discov. 2013 Apr;3(4):399-405
references.pmid: 23269703
references.citation: Nat Rev Mol Cell Biol. 2010 Feb;11(2):138-48
references.pmid: 20029420
references.citation: Trends Biochem Sci. 2012 Oct;37(10):418-24
references.pmid: 22836122
references.citation: Nat Genet. 1996 Dec;14(4):430-40
references.pmid: 8944023
references.citation: Lancet. 1997 May 24;349(9064):1505-10
references.pmid: 9167459
references.citation: Cancer Cell. 2012 Jul 10;22(1):106-16
references.pmid: 22789542
references.citation: Mol Cell. 1998 Sep;2(3):317-28
references.pmid: 9774970
references.citation: Mol Cell. 1999 Oct;4(4):511-8
references.pmid: 10549283
references.citation: J Clin Oncol. 2002 May 1;20(9):2310-8
references.pmid: 11981002
references.citation: Cancer Cell. 2007 Feb;11(2):103-5
references.pmid: 17292821
references.citation: Cancer Biol Ther. 2013 Jun;14(6):537-45
references.pmid: 23760496
references.citation: Cancer Res. 2012 Oct 1;72(19):4974-83
references.pmid: 22865450
references.citation: Cancer Res. 2006 Jan 1;66(1):41-5
references.pmid: 16397213
references.citation: Exp Cell Res. 2006 Oct 1;312(16):3120-31
references.pmid: 16860316
references.citation: J Clin Oncol. 2009 May 1;27(13):2163-9
references.pmid: 19307510
references.citation: Eur J Cancer. 2013 Sep;49(14):2972-8
references.pmid: 23810467
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
references.pmid: 11553815
references.citation: Mol Cell. 2011 Oct 21;44(2):235-51
references.pmid: 21963239
references.citation: Mol Cancer Res. 2007 Jan;5(1):35-45
references.pmid: 17259345
references.citation: J Clin Oncol. 2010 Mar 1;28(7):1145-53
references.pmid: 20100965
references.citation: Curr Biol. 2004 Jan 6;14(1):33-9
references.pmid: 14711411
references.citation: Cancer Cell. 2006 Dec;10(6):515-27
references.pmid: 17157791
references.citation: Int J Cancer. 2015 Jan 1;136(1):204-11
references.pmid: 24824628
references.citation: Mol Cell Biol. 2001 Jun;21(12):4005-15
references.pmid: 11359908
references.citation: Chromosoma. 2008 Aug;117(4):305-17
references.pmid: 18369654
references.citation: Science. 1994 Oct 7;266(5182):66-71
references.pmid: 7545954
references.citation: Clin Cancer Res. 2010 Dec 15;16(24):6159-68
references.pmid: 20802015
references.citation: Nat Struct Mol Biol. 2010 Jun;17(6):688-95
references.pmid: 20453858
references.citation: Cancer Cell. 2007 Aug;12(2):160-70
references.pmid: 17692807
references.citation: Mol Cell. 1999 Dec;4(6):1093-9
references.pmid: 10635334
references.citation: Biochem Soc Trans. 2012 Aug;40(4):768-72
references.pmid: 22817731
references.citation: J Biol Chem. 2000 Aug 4;275(31):23899-903
references.pmid: 10843985
references.citation: Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991-5
references.pmid: 6326095
references.citation: Cancer Discov. 2012 Aug;2(8):679-84
references.pmid: 22843421
references.citation: Ann Oncol. 2011 Apr;22(4):848-856
references.pmid: 20924076
references.citation: Mol Cell. 2012 Apr 27;46(2):125-35
references.pmid: 22445484