title: DEAD-box helicase DP103 defines metastatic potential of human breast cancers.
abstract: Despite advancement in breast cancer treatment, 30% of patients with early breast cancers experience relapse with distant metastasis. It is a challenge to identify patients at risk for relapse; therefore, the identification of markers and therapeutic targets for metastatic breast cancers is imperative. Here, we identified DP103 as a biomarker and metastasis-driving oncogene in human breast cancers and determined that DP103 elevates matrix metallopeptidase 9 (MMP9) levels, which are associated with metastasis and invasion through activation of NF-κB. In turn, NF-κB signaling positively activated DP103 expression. Furthermore, DP103 enhanced TGF-β-activated kinase-1 (TAK1) phosphorylation of NF-κB-activating IκB kinase 2 (IKK2), leading to increased NF-κB activity. Reduction of DP103 expression in invasive breast cancer cells reduced phosphorylation of IKK2, abrogated NF-κB-mediated MMP9 expression, and impeded metastasis in a murine xenograft model. In breast cancer patient tissues, elevated levels of DP103 correlated with enhanced MMP9, reduced overall survival, and reduced survival after relapse. Together, these data indicate that a positive DP103/NF-κB feedback loop promotes constitutive NF-κB activation in invasive breast cancers and activation of this pathway is linked to cancer progression and the acquisition of chemotherapy resistance. Furthermore, our results suggest that DP103 has potential as a therapeutic target for breast cancer treatment.
authors.forename: Eun Myoung
authors.initials: EM
authors.lastname: Shin
authors.forename: Hui Sin
authors.initials: HS
authors.lastname: Hay
authors.forename: Moon Hee
authors.initials: MH
authors.lastname: Lee
authors.forename: Jen Nee
authors.initials: JN
authors.lastname: Goh
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.forename: Yin Ping
authors.initials: YP
authors.lastname: Sen
authors.forename: See Wee
authors.initials: SW
authors.lastname: Lim
authors.forename: Einas M
authors.initials: EM
authors.lastname: Yousef
authors.forename: Hooi Tin
authors.initials: HT
authors.lastname: Ong
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Thike
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Kong
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Wu
authors.forename: Earnest
authors.initials: E
authors.lastname: Mendoz
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Chwee Teck
authors.initials: CT
authors.lastname: Lim
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lobie
authors.forename: Yoon Pin
authors.initials: YP
authors.lastname: Lim
authors.forename: Celestial T
authors.initials: CT
authors.lastname: Yap
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.forename: Martin B
authors.initials: MB
authors.lastname: Lee
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
authors.forename: Louis
authors.initials: L
authors.lastname: Gaboury
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Tan
authors.forename: Kam Man
authors.initials: KM
authors.lastname: Hui
authors.forename: George Wai-Cheong
authors.initials: GW
authors.lastname: Yip
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
mesh_terms: D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D055541:DEAD Box Protein 20 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D055541:DEAD Box Protein 20; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D000099151:MAP Kinase Kinase Kinase 7; C496560:IKBKB protein, human; C579270:MMP9 protein, human; C120168:DDX20 protein, human
references.citation: Eur J Cancer. 2000 Aug;36(13 Spec No):1621-30
references.pmid: 10959048
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18147-52
references.pmid: 15608061
references.citation: Genes Chromosomes Cancer. 2011 Oct;50(10):837-47
references.pmid: 21769958
references.citation: Curr Probl Cancer. 2002 Sep-Oct;26(5):282-309
references.pmid: 12429950
references.citation: Cell. 2002 Apr;109 Suppl:S81-96
references.pmid: 11983155
references.citation: Genes Dev. 2010 Dec 15;24(24):2800-11
references.pmid: 21159820
references.citation: Genes Cells. 1996 Mar;1(3):325-36
references.pmid: 9133666
references.citation: Nat Cell Biol. 2006 Sep;8(9):986-93
references.pmid: 16906147
references.citation: Nat Cell Biol. 2010 Aug;12(8):758-67
references.pmid: 20622870
references.citation: Cell Cycle. 2008 Dec;7(23):3759-67
references.pmid: 19029824
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16940-5
references.pmid: 17939994
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13550-5
references.pmid: 16141321
references.citation: Mol Cell Biol. 2003 Aug;23(16):5738-54
references.pmid: 12897145
references.citation: Biostatistics. 2007 Jan;8(1):118-27
references.pmid: 16632515
references.citation: Mol Cell Biol. 2005 Mar;25(5):1879-90
references.pmid: 15713642
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17372-7
references.pmid: 16301532
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references.pmid: 11752295
references.citation: Cell. 2002 Apr 19;109(2):169-80
references.pmid: 12007404
references.citation: Nat Cell Biol. 2005 Aug;7(8):758-65
references.pmid: 16056267
references.citation: Nat Rev Cancer. 2006 Oct;6(10):776-88
references.pmid: 16990855
references.citation: Oncogene. 2011 Apr 7;30(14):1615-30
references.pmid: 21170083
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Chem Biol Interact. 2010 Mar 30;184(3):403-12
references.pmid: 20093109
references.citation: Nat Rev Cancer. 2003 Jan;3(1):55-63
references.pmid: 12509767
references.citation: Mol Biochem Parasitol. 2000 Feb 25;106(1):51-61
references.pmid: 10743610
references.citation: Cell Res. 2011 Jan;21(1):116-30
references.pmid: 21187855
references.citation: J Cell Biol. 1999 Dec 13;147(6):1181-94
references.pmid: 10601333
references.citation: Amino Acids. 2011 Jul;41(2):271-90
references.pmid: 20640864
references.citation: Immunol Rev. 2012 Mar;246(1):95-106
references.pmid: 22435549
references.citation: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references.pmid: 12582260
references.citation: Mol Cell. 2009 Dec 11;36(5):831-44
references.pmid: 20005846
references.citation: Nat Rev Cancer. 2012 Jan 19;12(2):121-32
references.pmid: 22257950
references.citation: BMC Genomics. 2008 May 22;9:239
references.pmid: 18498629
references.citation: Mol Pharmacol. 2008 Mar;73(3):919-29
references.pmid: 18065684
references.citation: Cancer Res. 2008 May 15;68(10):3959-69
references.pmid: 18483282
references.citation: Mol Cancer. 2011 Feb 22;10:22
references.pmid: 21342498
references.citation: Breast Cancer Res. 2010;12(5):R68
references.pmid: 20813035
references.citation: BMC Cancer. 2010 Jun 09;10:270
references.pmid: 20534121
references.citation: Breast Cancer Res Treat. 2004 Jul;86(2):139-52
references.pmid: 15319566
references.citation: Lancet. 2011 Oct 22;378(9801):1461-84
references.pmid: 21924486
references.citation: Cell Death Differ. 2006 May;13(5):738-47
references.pmid: 16485028
references.citation: Breast Cancer Res. 2005;7(6):R953-64
references.pmid: 16280042
references.citation: Genes Dev. 1995 Nov 15;9(22):2723-35
references.pmid: 7590248
references.citation: Cell Cycle. 2006 May;5(9):1001-7
references.pmid: 16639080
references.citation: Nucleic Acids Res. 2006;34(15):4168-80
references.pmid: 16936318
references.citation: Nat Rev Cancer. 2005 Aug;5(8):591-602
references.pmid: 16056258
references.citation: Nat Cell Biol. 2012 Dec;14(12):1270-81
references.pmid: 23159929
references.citation: Am J Pathol. 1996 Jan;148(1):313-9
references.pmid: 8546221
references.citation: Transl Oncol. 2010 Aug 01;3(4):218-29
references.pmid: 20689763
references.citation: Cancer Prev Res (Phila). 2012 Apr;5(4):631-43
references.pmid: 22369852
references.citation: Cell. 2003 Nov 26;115(5):565-76
references.pmid: 14651848
references.citation: Nat Rev Clin Oncol. 2011 Mar 01;8(4):210-21
references.pmid: 21364524
references.citation: Mol Cell Biol. 2003 Jan;23(1):414-23
references.pmid: 12482992
references.citation: Bioessays. 2007 Oct;29(10):1039-47
references.pmid: 17876798
references.citation: Nat Immunol. 2011 Jul 19;12(8):715-23
references.pmid: 21772280
references.citation: Mol Cancer Ther. 2005 May;4(5):814-23
references.pmid: 15897246
references.citation: EMBO J. 2008 Jul 23;27(14):1963-73
references.pmid: 18583959
references.citation: J Clin Oncol. 2007 Apr 1;25(10):1239-46
references.pmid: 17401012
references.citation: J Clin Invest. 1997 Dec 15;100(12):2952-60
references.pmid: 9399940
references.citation: Nat Rev Clin Oncol. 2010 Dec;7(12):693-701
references.pmid: 20956980
references.citation: CA Cancer J Clin. 2011 Nov-Dec;61(6):409-18
references.pmid: 21969133
references.citation: Genes Dev. 2004 Sep 15;18(18):2195-224
references.pmid: 15371334
references.citation: Nature. 2006 May 25;441(7092):431-6
references.pmid: 16724054
references.citation: Blood. 2005 May 1;105(9):3722-30
references.pmid: 15650054
references.citation: Oncogene. 2002 Mar 27;21(13):2066-78
references.pmid: 11960379
references.citation: Cancer Res. 2007 Jan 15;67(2):659-64
references.pmid: 17234776
references.citation: Nat Rev Cancer. 2002 Mar;2(3):161-74
references.pmid: 11990853
references.citation: Eur J Cancer. 1998 Feb;34(2):214-21
references.pmid: 9741324
references.citation: Nature. 2008 Jan 10;451(7175):147-52
references.pmid: 18185580
references.citation: Mol Cell. 2011 Jul 22;43(2):180-91
references.pmid: 21777808
references.citation: Mol Cell. 2010 Oct 8;40(1):75-86
references.pmid: 20932476
references.citation: Int J Biochem Cell Biol. 2007;39(9):1582-92
references.pmid: 17572133
references.citation: PLoS One. 2010 Jun 09;5(6):e11030
references.pmid: 20543960
references.citation: Trends Mol Med. 2013 Aug;19(8):487-500
references.pmid: 23746697
references.citation: J Biol Chem. 2004 Mar 5;279(10):9056-63
references.pmid: 14699164
references.citation: Br J Surg. 2011 Nov;98(11):1561-5
references.pmid: 22059233
references.citation: J Biol Chem. 1999 Jul 2;274(27):19136-44
references.pmid: 10383418
references.citation: Cancer Res. 2011 Nov 1;71(21):6728-37
references.pmid: 21875943
references.citation: Science. 2011 Mar 25;331(6024):1559-64
references.pmid: 21436443
references.citation: Endocr Relat Cancer. 2004 Dec;11(4):643-58
references.pmid: 15613444
references.citation: J Cell Sci. 2005 May 15;118(Pt 10):2143-53
references.pmid: 15855236
references.citation: Cancer. 2004 Jan 15;100(2):356-65
references.pmid: 14716772
references.citation: Int J Cancer. 2000 Apr 15;86(2):188-96
references.pmid: 10738245
references.citation: Nature. 2009 Mar 26;458(7237):430-7
references.pmid: 19325622
references.citation: Mol Endocrinol. 2001 Jan;15(1):69-79
references.pmid: 11145740
references.citation: Cancer Res. 2011 Oct 15;71(20):6463-74
references.pmid: 21868760
references.citation: Nucleic Acids Res. 2006;34(15):4206-15
references.pmid: 16935882
references.citation: Cell. 2006 Nov 17;127(4):679-95
references.pmid: 17110329
references.citation: Oncogene. 2006 Oct 30;25(51):6817-30
references.pmid: 17072330
references.citation: Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
references.pmid: 17183360
references.citation: Mol Cancer. 2011 Jan 28;10(1):10
references.pmid: 21276221
references.citation: Rev Endocr Metab Disord. 2007 Sep;8(3):199-213
references.pmid: 17657606
references.citation: Endocrinology. 2008 May;149(5):2168-75
references.pmid: 18258677
references.citation: Trends Biochem Sci. 2013 Sep;38(9):426-34
references.pmid: 23932019
references.citation: Cold Spring Harb Perspect Biol. 2010 Jun;2(6):a000109
references.pmid: 20516126
references.citation: Nat Rev Clin Oncol. 2010 Nov;7(11):641-51
references.pmid: 20808302
references.citation: Oncology (Williston Park). 2011 Nov 15;25(12):1158-64
references.pmid: 22229207
references.citation: Hum Mol Genet. 2000 Aug 12;9(13):1977-86
references.pmid: 10942426