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QSOX1 Expression Is Associated with Aggressive Tumor Features and Reduced Survival in Breast Carcinomas

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QSOX1 Expression Is Associated with Aggressive Tumor Features and Reduced Survival in Breast Carcinomas Modern Pathology (2016) 29, 1485–1491 © 2016 USCAP, Inc All rights reserved 0893-3952/16 $32.00 1485 QSOX1 expression is associated with aggressive tumor features and reduced survival in breast carcinomas Gøril Knutsvik1,2, Karin Collett2, Jarle Arnes1,2, Lars A Akslen1,2 and Ingunn M Stefansson1,2 1Centre for Cancer Biomarkers, CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway and 2Department of Pathology, Haukeland University Hospital, Bergen, Norway The biological role of quiescin sulfhydryl oxidase 1 (QSOX1) in tumor development is not well known, and its relation to breast cancer progression and prognosis is controversial. Here, our aim was to study the expression pattern and prognostic impact of QSOX1 in breast cancer, in relation to molecular subgroups and tumor cell proliferation. We examined a population-based series as part of the prospective Norwegian Breast Cancer Screening Program, including all women (50–69 years) diagnosed with breast cancer in one county of Norway during 1996–2003. QSOX1 expression was assessed by immunohistochemistry on tissue microarrays (n = 458). Median follow-up time was 13 years. High expression of QSOX1 protein was associated with features of poor prognosis including high histologic grade, hormone receptor negativity, HER2 positivity, and increased tumor cell proliferation. High QSOX1 expression was further associated with reduced breast cancer-specific survival in both univariate and multivariate analysis, independent of molecular subtypes. High QSOX1 expression is a strong and independent factor of reduced survival in breast cancer, also reflected by elevated levels in more aggressive molecular subgroups. QSOX1 expression may represent a biomarker for aggressive disease and a potential treatment target. Modern Pathology (2016) 29, 1485–1491; doi:10.1038/modpathol.2016.148; published online 26 August 2016 Breast cancer is the most common type of malignant in breast and pancreatic cell lines.11,12 Secreted tumors among women, and despite advances in QSOX1 may also have an important role in diagnosis and therapy, it is a major cause of illness creating a pro-invasive environment.2 and death. Thus, it is important to explore the However, the prognostic impact of QSOX1 clinical relevance of novel biomarkers and possible expression in breast cancer remains controversial. treatment targets. One report showed that high QSOX1 mRNA Quiescin sulfhydryl oxidase (QSOX1) is an expression was associated with an adverse prognosis 11 enzyme mainly localized to the Golgi apparatus.1,2 in Luminal B breast cancer. In contrast to this, high QSOX1 mRNA expression has been correlated It catalyzes disulfide bond formation in proteins 13 during folding, with concurrent reduction of oxygen with favorable outcome. Thus, the value of QSOX1 expression as a prognostic biomarker in to hydrogen peroxide.3 QSOX1 is also secreted, and breast cancer remains undetermined. highest expression has been shown in secretory 4 On this background, our aim was to study the cells. expression of QSOX1 in a well-defined population- Although previously associated with fibroblast based series of breast cancers, with clinico- quiescence,5 it has become increasingly clear that 6 pathologic associations and prognostic impact as QSOX1 is also related to malignancy. Elevated end points. Second, we wanted to assess QSOX1 QSOX1 expression has been shown in prostate, expression in relation to tumor cell proliferation and 7–10 breast, and pancreatic cancer, and high levels molecular subgroups of breast cancer. have been associated with an invasive phenotype Correspondence: IM Stefansson, MD, PhD, Centre for Cancer Materials and methods Biomarkers, CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen N-5021, Norway. Patient Series E-mail: [email protected] Received 23 March 2016; revised 8 July 2016; accepted 8 July A population-based series of 534 breast carcinomas 2016; published online 26 August 2016 was studied.14 In brief, women aged 50–69 years www.modernpathology.org QSOX1 in breast cancer 1486 G Knutsvik et al diagnosed with primary breast carcinoma during Inc., Rosemont, IL, USA), corresponding to pre- 1996–2003 as part of the prospective Norwegian viously published protocols aside from a small Breast Cancer Screening Program were included. adjustment of concentration.10–13 Detection was The patients received treatment according to done by Dako EnVision rabbit for 30 min. standard protocols at the time. Follow-up information was provided by the Norwegian Cause CK5/6. Staining procedures were performed using of Death Registry, and can be considered accurate the K4061/Envision Dual Link System (rabbit and complete. Last date of follow-up was 31 +mouse). Slides were incubated for 30 min with a December 2011. Outcome data include survival mouse monoclonal antibody (Dako M7237, clone status, survival time, and cause of death. During D5/16 B4) at a 1:200 dilution.16 the follow-up period, 79 patients (15%) died from breast carcinoma, and 62 (12%) died from other causes. The median follow-up was 13 years P-cadherin. P-cadherin staining was obtained by calculated by the reverse Kaplan–Meier method. incubating sections for 60 min with a mouse This study was approved by the Western Regional monoclonal antibody (clone 56) from BD Biosciences (San Jose, CA, USA) at a dilution of 1: Committee for Medical and Health Research Ethics, 15,17 REC West (REK 2012/1704). 400. Detection was done by Dako Envision mouse for 30 min. Sections were developed in DAB chromogen (Dako REAL DAB+chromogen) and Clinico-Pathological Variables counterstained with Dako REAL hematoxylin. For QSOX1, sections from a breast carcinoma The following variables were recorded: age at known to yield positive staining were used as diagnosis, tumor diameter, histologic type, histologic controls. For CK5/6 and P-cadherin; tonsillar tissue grade, lymph node status, and hormonal receptor was used as positive control. Negative controls were status. Mitotic count was done separately and obtained by replacing the primary antibody with reported as mitoses per mm2. Furthermore, selected Tris-buffered saline. results of previously investigated biomarkers (HER2, Ki67) were included.14 Of 534 patients in the complete cohort, tissue microarrays were available for 458 patients (86%). Evaluation of Staining Tissue microarrays were examined and scored Tissue Microarrays by one pathologist (GK) blinded to patient characteristics and outcome. Staining was recorded H&E-stained slides were used for tumor verification, 14 by use of a semi-quantitative and subjective grading as previously described. In brief, 1.0 mm cores in system as previously described.18,19 In brief, a triplicate were punched and mounted into a staining index (values 0–9) was calculated as recipient paraffin block using a semiautomated a product of staining intensity (0–3) and proportion precision instrument (Minicore 3, Tissue Arrayer, of tumor cells showing a positive reaction (0 = no Alphelys, France). Areas of high tumor purity, staining, 1o10%, 2 = 10–50% and 3450%). In the tumor periphery and the highest histologic grade subsequent statistical analyses, cutoff points were were selected. 190 cases had previously been mainly based upon median or quartile values, also processed;15 from these cases three tissue cores with considering the frequency distribution for each a diameter of 0.6 mm were obtained by a different marker. Categories with similar survival estimates instrument (Beecher Instruments, Silver Spring, were merged. MD, USA). QSOX1 staining was cytoplasmic with a granular, dot-like appearance. In some sections a weak, cytoplasmic staining of normal breast epithelium, Immunohistochemistry endothelium, stromal cells, and lymphocytes was Staining was performed on thin tissue microarray noted. There are no validated QSOX1 cutoff points sections (5 μm) from formalin-fixed and paraffin- based on immunohistochemical staining. In this embedded tumor tissue. The sections were de-waxed study, QSOX1 low expression encompassed with xylene/ethanol before target retrieval in a carcinomas showing weak to moderate staining microwave oven (6th Sense) in Target Retrieval and/or more focal staining (staining index 0–6). Solution (pH = 6) for 20 min. Endogenous peroxidase QSOX1 high expression was denoted in cases activity was blocked. Staining procedures were demonstrating strong cytoplasmic staining intensity performed using a DAKO autostainer. in 50% or more of the tumor cells (staining index 9). CK5/6 positivity was cytoplasmic. P-cadherin QSOX1. Sections were incubated for 60 min at staining was mainly membranous, although some room temperature (22 °C) with a rabbit polyclonal cytoplasmic staining was observed in cases showing QSOX1 antibody diluted 1:100 (Proteintech Group, strong overall staining. Modern Pathology (2016) 29, 1485–1491 QSOX1 in breast cancer G Knutsvik et al 1487 For CK5/6, a positive staining was defined as assess the agreement of categorical scores. Ordinal staining index40, whereas for P-cadherin, staining variables were compared between two or more index43 was used, as previously described.15,20 groups using Mann–Whitney U or Kruskal–Wallis One observer (GK) assessed the series twice, with H-tests. good intra-observer reproducibility, Kappa-value For survival analyses, the end point was breast 0.89, Po0.001. For QSOX1, a subset (n = 66) was cancer-specific survival, defined as the time in scored by two observers
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