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High TNFRSF12A Level Associated with MMP-9 Overexpression Is RESEARCH ARTICLE High TNFRSF12A level associated with MMP-9 overexpression is linked to poor prognosis in breast cancer: Gene set enrichment analysis and validation in large-scale cohorts Jungho Yang1, Kyueng-Whan Min2*, Dong-Hoon Kim1*, Byoung Kwan Son3, Kyoung Min Moon4, Young Chan Wi5, Seong Sik Bang5, Young Ha Oh2, Sung-Im Do1, Seoung Wan Chae1, Sukjoong Oh6, Young Hwan Kim7, Mi Jung Kwon8 a1111111111 1 Departments of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, a1111111111 Seoul, Republic of Korea, 2 Department of Pathology, Hanyang University Guri Hospital, Hanyang University a1111111111 College of Medicine, Guri, Gyeonggi-do, Republic of Korea, 3 Department of Internal Medicine, Eulji Hospital, a1111111111 Eulji University School of Medicine, Seoul, Republic of Korea, 4 Department of Internal Medicine, Gangneung a1111111111 Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea, 5 Department of Pathology, Hanyang University College of Medicine, Seoul, Republic of Korea, 6 Departments of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 7 Departments of Nuclear Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 8 Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do, Republic of Korea OPEN ACCESS * [email protected](KWM); [email protected](DHK) Citation: Yang J, Min K-W, Kim D-H, Son BK, Moon KM, Wi YC, et al. (2018) High TNFRSF12A level associated with MMP-9 overexpression is linked to poor prognosis in breast cancer: Gene set Abstract enrichment analysis and validation in large-scale cohorts. PLoS ONE 13(8): e0202113. https://doi. org/10.1371/journal.pone.0202113 Background Editor: Aamir Ahmad, University of South Alabama Mitchell Cancer Institute, UNITED STATES Matrix metalloproteinase-9 (MMP-9) is associated with remodelling of the extracellular matrix and invasion in various cancers. Identifying proteins connected to high MMP-9 Received: March 20, 2018 expression is important in explaining its mechanisms. Our study aims to shed light on genes Accepted: July 27, 2018 associated with high MMP-9 expression and to discuss their clinical impact in breast cancer. Published: August 24, 2018 Copyright: © 2018 Yang et al. This is an open Methods access article distributed under the terms of the Creative Commons Attribution License, which We evaluated 173 breast cancer cases from the Kangbuk Samsung Hospital, with 1964 permits unrestricted use, distribution, and cases from the Molecular Taxonomy of Breast Cancer International Consortium database reproduction in any medium, provided the original serving as a validation cohort. We investigated relationships between MMP-9 expression author and source are credited. and clinicopathological characteristics. We then used gene set enrichment analyses to Data Availability Statement: The Ethics detect the association of genes with MMP-9 overexpression, and performed survival analy- Committee of the Kangbuk Samsung Hospital (Tel: +82-2-2001-1943) approved the study and ses to determine the significance of the gene in three independent cohorts. imposed legal restrictions according to the ªPersonal Information Protection Actº in South Korea. Data is available upon request to Results researchers qualified to handle confidential High MMP-9 expression correlated with poor prognosis in univariate and multivariate analy- information. To request data access, please contact Kangbuk Samaung Hospital Institutional Review ses. Using gene set enrichment analysis, we found that tumour necrosis factor receptor Board ([email protected]). superfamily member 12A (TNFRSF12A) was linked to high MMP-9 expression. In the PLOS ONE | https://doi.org/10.1371/journal.pone.0202113 August 24, 2018 1 / 13 MMP-9 expression in breast cancer Funding: This paper was supported by the Bumsuk survival analysis of three published data sets (METABRIC, GSE1456, GSE20685), high Academic Research Fund in 2017. TNFRSF12A was relevant to a poor survival rate. Competing interests: The authors have declared that no competing interests exist. Conclusions High levels of TNFRSF12A associated with MMP-9 overexpression may be important to explain the progression of breast cancer, and survival could be improved using therapy tar- geting TNFRSF12A. Introduction Breast cancer is one of the most common types of cancer diagnosed and main cause of death from cancer among women (23% of all cancer cases, 14% of deaths from cancer) [1]. Invasive ductal carcinoma (IDC) represents 70 to 80 percent of all breast cancer cases, followed by lobu- lar carcinoma, tubular/cribriform carcinoma, mucinous carcinoma, medullary carcinoma, and papillary carcinoma [2]. Several findings, such as cancer development, cancer stage, oes- trogen receptor (ER) and progesterone receptor (PR) expression, human epithelial growth fac- tor receptor 2 (HER2) gene amplification, p53 overexpression, and BRCA1 and BRCA2 mutations, are taken into account in the development, treatment, and management of breast cancer [3]. Recently, in molecular subtyping using the above markers, breast cancer was classi- fied into five major subtypes: luminal A, luminal B HER2-negative, luminal B HER2-positive, basal-like, and HER2-positive [4]. Matrix metalloproteinases (MMPs) is critical in decomposition of the extracellular mem- brane (ECM), including the basement membrane, a specialized matrix comprising type IV col- lagen, laminin, entactin, proteoglycans, and glycosaminoglycans [5]. Twenty-five MMPs have been identified to play critical roles in cancer progression via many carcinogenic processes, including remodelling of the microenvironment. Recently, studies on treatments targeting MMP-2 have also been reported [6,7]. MMP-9, a member of the MMPs, has long been postulated to play an important role in poor prognosis in tumour cells [8]. MMP-9 causes the release of the biologically active form of vascular endothelial growth factor, which is critical in angiogenesis [9,10]. The process is com- pleted by the direct proteolytic degradation of vascular basement membrane proteins, mean- ing that MMP-9 can be essential in the creation of new blood vessels [10]. MMP-9 degrades the collagen-rich ECM, which has been related to cancer invasiveness, metastasis, and recur- rence [11,12]. Therefore, MMP-9 has been considered an important prognostic predictor in various tumours. In previous studies, MMP-9 was reported to be overexpressed in aggressive tumours [13± 15]. Additionally, MMP-9 is required for endothelial cell migration and tube formation, and is likely to be important in cerebral angiogenesis [16]. Thus, an increase in MMP-9 levels associ- ated with vascular angiogenesis could promote tumour invasion and metastasis. MMP-9 is involved in a variety of developmental processes because of its important role in angiogenesis. MMP-9 deficiency leads to bone development disorders, particularly bone formation delay caused by insufficient angiogenesis in the growth plate [17]. Recent studies demonstrated that MMP-9 could be involved in natural killer (NK) cell dysfunction by promoting tumour immune avoidance. Hence, the effect of NK cell-based immunotherapy could be enhanced by controlling MMP-9 activity [18]. PLOS ONE | https://doi.org/10.1371/journal.pone.0202113 August 24, 2018 2 / 13 MMP-9 expression in breast cancer The present study aimed to assess whether MMP-9 levels could predict patient survival and to analyse its prognostic value in comparison with the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database. We further aimed to investigate the prog- nostic utility of MMP-9 in two cohorts (our data and METABRIC data), and to identify genes associated with MMP-9 overexpression using gene set enrichment analysis (GSEA). In addi- tion, survival analysis was performed to confirm the clinical significance of the newly identi- fied genes (Fig 1). Materials and methods Patient selection This study included patients who were treated with breast cancer at Kangbuk Samsung Medi- cal Center in Korea between 2000 and 2005. In randomly selected patients, immunohisto- chemical staining was performed on 173 specimens obtained from surgical treatment. The Reporting Recommendations for Tumour Marker Prognostic Studies (REMARK) criteria were followed throughout this study. The inclusion criteria were: 1) patients with histopatho- logical evidence of primary invasive ductal carcinoma confirmed by pathologists, and known clinical outcome; and 2) patients without preoperative concurrent chemoradiotherapy. The mean age of the patients was 47 (range: 25±79) years. Treatments comprised 163 (94.2%) modified radical mastectomies with axillary lymph node dissection and 10 (5.8%) breast-conserving surgeries. At the time of surgery, the T and N stages, according to the 8th American Joint Committee on Cancer (AJCC), were distributed as follows: T1, 61 (35.3%); T2, 100 (57.8%); T3, 11 (6.4%), T4, 1 (0.6%); N0, 68 (39.3%); N1, 62 (35.8%); N2, 23 (13.3%); and N3, 20 (11.6%). The distribution of AJCC stages was as follows: stage I, 31 (17.9%); stage II, 97 (56.1%); and stage III, 45 (26%). Haematoxylin and eosin (H&E)-stained slides were reviewed by at least two pathologists for each case (Min and Kim). The tumours were characterized according to their clinicopatho- logical features, such as size, margins, number of tumours (single
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