Abstract
IntroductionQuiescin 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.MethodsCorrelation 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.ResultsGOBO 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.ConclusionsTaken 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.
Highlights
Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins
Expression of QSOX1 was significantly higher in estrogen receptor (ER)+ tumors compared to ER- (P-value < 0.00001), with the highest expression observed in Luminal A, Luminal B and Normal-like subtypes (Figure 1a, b)
While elevated QSOX1 expression is not associated with survival when considering all breast tumor subtypes together, it is highly associated with poor relapse free survival (RFS) (P = 0.00062) and overall survival (OS) (P = 0.00031) in Luminal B tumors (Figure 1c, d)
Summary
Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. To determine if QSOX1 overexpression may be functionally relevant in other tumor types we performed immunohistochemistry (IHC) on breast tissue microarrays and discovered that the expression of QSOX1 is specific to malignant breast tumors as well, and has diagnostic and prognostic significance in publicly available microarray datasets. These findings led us to hypothesize that overexpression of QSOX1 might be functionally conserved between pancreatic ductal adenocarcinoma and breast adenocarcinoma, prompting further exploration of the potential malignant function of QSOX1
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