Wantanabe, Aprill

Abstract Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. Informatic analysis using the newly available “Gene Expression Based Outcome for Breast Cancer Online” (GOBO) tool indicated high levels of QSOX1 expression in Estrogen Receptor positive (ER+) subtypes of breast cancer. We confirmed this finding by evaluation of QSOX1 protein expression in breast tumors and in a panel of breast cancer cell lines. In addition, Kaplan Meyer analyses revealed QSOX1 as a significant predictive marker for both relapse and poor overall survival in Luminal B tumors, but not in other intrinsic subtypes. To investigate malignant cell mechanisms in which QSOX1 might play a key role, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in ER+ MCF7 and ER− BT549 breast cancer cell lines. Suppression of QSOX1 protein dramatically slowed cell proliferation but did not significantly effect apoptosis or cell cycle regulation. Inhibition of QSOX1 did however dramatically inhibit MCF7 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 activation of MMP-9 a key mediator of breast cancer invasive behavior. 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-invasive role in malignant progression through post-translational activation of MMP-9. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-04.

Abstract Quiescin-sulfhydryl oxidase (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. We previously mapped a peptide in plasma from pancreatic ductal adenocarcinoma patients back to an overexpressed QSOX1 parent protein in tumor cells. It is not known why, or in what capacity, pancreatic tumors overexpress QSOX1. To begin to address this question, we first showed through immunohistochemistry that QSOX1 is overexpressed in patients diagnosed with pancreatic cancer, while it is not expressed in adjacent normal tissue or infiltrating lymphocytes. To determine the potential advantages QSOX1 might provide to tumor cells we knocked down QSOX1 using shRNA that suppressed both short and long isoforms of the protein. Loss of QSOX1 expression suppressed cell growth over time, while changes in cell cycle and apoptotic markers were minimal. However, QSOX1 shRNA dramatically inhibited the abilities of BxPC3 and Panc-1 pancreatic tumor cells to invade through Matrigel in a modified Boyden chamber assay. Mechanistically, gelatin zymography indicated that QSOX1 may play an important role in intracellular processing and extracellular activation of MMP-2 and MMP-9. Taken together, our results suggest that pancreatic tumors that express QSOX1 demonstrate an invasive phenotype through MMP activation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B60.