title: Expression of quiescin sulfhydryl oxidase 1 is associated with a highly invasive phenotype and correlates with a poor prognosis in Luminal B breast cancer.
abstract: BACKGROUND
  Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. Tumor specific expression of QSOX1 has been reported for numerous tumor types. In this study, we investigate QSOX1 as a marker of breast tumor progression and evaluate the role of QSOX1 as it relates to breast tumor growth and metastasis.
  
  
  METHODS
  Correlation of QSOX1 expression with breast tumor grade, subtype and estrogen receptor (ER) status was gathered through informatic analysis using the "Gene expression based Outcome for Breast cancer Online" (GOBO) web-based tool. Expression of QSOX1 protein in breast tumors tissue microarray (TMA) and in a panel of breast cancer cell lines was used to confirm our informatics analysis. To investigate malignant cell mechanisms for which QSOX1 might play a key role, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in ER+ Luminal A-like MCF7, ER+ Luminal B-like BT474 and ER- Basal-like BT549 breast cancer cell lines.
  
  
  RESULTS
  GOBO analysis revealed high levels of QSOX1 RNA expression in ER+ subtypes of breast cancer. In addition, Kaplan Meyer analyses revealed QSOX1 RNA as a highly significant predictive marker for both relapse and poor overall survival in Luminal B tumors. We confirmed this finding by evaluation of QSOX1 protein expression in breast tumors and in a panel of breast cancer cell lines. Expression of QSOX1 in breast tumors correlates with increasing tumor grade and high Ki-67 expression. Suppression of QSOX1 protein slowed cell proliferation as well as dramatic inhibition of MCF7, BT474 and BT549 breast tumor cells from invading through Matrigel™ in a modified Boyden chamber assay. Inhibition of invasion could be rescued by the exogenous addition of recombinant QSOX1. Gelatin zymography indicated that QSOX1 plays an important role in the function of MMP-9, a key mediator of breast cancer invasive behavior.
  
  
  CONCLUSIONS
  Taken together, our results suggest that QSOX1 is a novel biomarker for risk of relapse and poor survival in Luminal B breast cancer, and has a pro-proliferative and pro-invasive role in malignant progression partly mediated through a decrease in MMP-9 functional activity.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Katchman
authors.forename: I Tolgay
authors.initials: IT
authors.lastname: Ocal
authors.forename: Heather E
authors.initials: HE
authors.lastname: Cunliffe
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Chang
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.forename: Aprill
authors.initials: A
authors.lastname: Watanabe
authors.forename: Janine
authors.initials: J
authors.lastname: LoBello
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Lake
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology*; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000401:mortality / Q000473:pathology*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D020780:Matrix Metalloproteinase 9; D050862:Oxidoreductases Acting on Sulfur Group Donors; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C117183:QSOX1 protein, human; C579270:MMP9 protein, human
references.citation: J Comp Neurol. 2004 May 31;473(3):334-63
references.pmid: 15116395
references.citation: J Endocrinol. 2004 Nov;183(2):353-63
references.pmid: 15531723
references.citation: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references.pmid: 22237781
references.citation: Semin Cell Dev Biol. 2010 Sep;21(7):663
references.pmid: 20430106
references.citation: J Clin Invest. 2011 Oct;121(10):3786-8
references.pmid: 21965334
references.citation: Integr Biol (Camb). 2011 Apr;3(4):279-96
references.pmid: 21340093
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
references.pmid: 11553815
references.citation: Oncogene. 2009 Sep 17;28(37):3307-19
references.pmid: 19597465
references.citation: Eur J Cancer. 2008 Dec;44(18):2760-5
references.pmid: 19026532
references.citation: J Proteome Res. 2009 Oct;8(10):4722-31
references.pmid: 19795908
references.citation: FEBS Lett. 2010 Apr 16;584(8):1521-5
references.pmid: 20211621
references.citation: Breast Cancer Res. 2010;12(6):R96
references.pmid: 21080941
references.citation: PLoS One. 2011 Mar 21;6(3):e17911
references.pmid: 21445301
references.citation: J Mammary Gland Biol Neoplasia. 2010 Jun;15(2):201-12
references.pmid: 20440544
references.citation: Mol Cancer Res. 2011 Dec;9(12):1621-31
references.pmid: 21989104
references.citation: Cancer Prev Res (Phila). 2010 Nov;3(11):1361-4
references.pmid: 20959519
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Nature. 2012 Aug 16;488(7411):414-8
references.pmid: 22801504
references.citation: BMC Cancer. 2009 Jun 16;9:188
references.pmid: 19531263
references.citation: Biochem J. 2007 Jun 15;404(3):403-11
references.pmid: 17331072
references.citation: Cell. 2010 Apr 2;141(1):52-67
references.pmid: 20371345
references.citation: Genomics. 1998 Dec 15;54(3):460-8
references.pmid: 9878249
references.citation: Cancer Res. 1990 Sep 15;50(18):6087-94
references.pmid: 1697506
references.citation: Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):300-11
references.pmid: 16677076
references.citation: Nature. 2000 Aug 17;406(6797):747-52
references.pmid: 10963602
references.citation: Cancer Res. 2008 Mar 1;68(5):1378-87
references.pmid: 18316601
references.citation: Biochemistry. 2008 Apr 29;47(17):4955-63
references.pmid: 18393449
references.citation: Annu Rev Pathol. 2010;5:193-221
references.pmid: 19824828
references.citation: Arch Biochem Biophys. 2002 Sep 1;405(1):1-12
references.pmid: 12176051
references.citation: Cancer Res. 1990 Sep 15;50(18):6075-86
references.pmid: 1975513
references.citation: Annu Rev Pathol. 2008;3:221-47
references.pmid: 18233952
references.citation: Exp Cell Res. 2007 Nov 15;313(19):3971-82
references.pmid: 17927979
references.citation: J Mol Histol. 2008 Apr;39(2):217-25
references.pmid: 18034316
references.citation: PLoS One. 2008 Aug 20;3(8):e2994
references.pmid: 18714348
references.citation: Biochim Biophys Acta. 2012 Jan;1825(1):29-36
references.pmid: 22020293
references.citation: Int J Mol Sci. 2012;13(5):5607-27
references.pmid: 22754319