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The Novel Sugar Transporter SLC50A1 As a Potential Serum-Based Diagnostic and Prognostic Biomarker for Breast Cancer

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The Novel Sugar Transporter SLC50A1 As a Potential Serum-Based Diagnostic and Prognostic Biomarker for Breast Cancer Journal name: Cancer Management and Research Article Designation: Original Research Year: 2019 Volume: 11 Cancer Management and Research Dovepress Running head verso: Wang et al Running head recto: SLC50A1: a serum-based biomarker for breast cancer open access to scientific and medical research DOI: http://dx.doi.org/10.2147/CMAR.S190591 Open Access Full Text Article ORIGINAL RESEARCH The novel sugar transporter SLC50A1 as a potential serum-based diagnostic and prognostic biomarker for breast cancer Yu Wang1 Background: The novel sugar transporter and membrane protein SLC50A1 has been identified Yao Shu2 as a potential candidate biomarker for breast cancer; however, its potential as a serum biomarker Congyang Gu3 for breast cancer detection and prognosis is unclear. The aim of this study was to investigate Yu Fan4 the serum expression profile of SLC50A1 and to determine its diagnostic and prognostic sig- nificance in breast cancer. 1Department of Health Examination, The Affiliated Hospital of Southwest Materials and methods: Bioinformatics analysis was conducted, and data for SLC50A1 Medical University, Luzhou, Sichuan expression in human breast cancer were collected. Semi-quantitative real-time PCR and ELISA 2 Province, China; Department of were performed to compare SLC50A1 expression in several breast cancer cell lines, one paired Geriatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, tissue cohort (n=20) and two independent cohorts of human breast cancer patients (n=85) and Sichuan Province, China; 3Department healthy individuals (n=30). The results were analyzed statistically, and associations between of Pathology, The First People’s clinicopathological and survival data were evaluated by multivariate Cox regression analysis. Hospital of Neijiang City, Neijiang, Sichuan Province, China; 4Department Results: SLC50A1 was confirmed as a candidate breast cancer gene by bioinformatics analysis. of Oncology, The Affiliated Hospital of SLC50A1 mRNA expression levels were significantly upregulated in breast cancer (P<0.001). Southwest Medical University, Luzhou, Serum SLC50A1 levels were able to discriminate between women with breast cancer and Sichuan Province, China healthy women with a sensitivity of 75.3% and a specificity of 100.0% (P<0.001; area under the curve=0.915). Interestingly, SLC50A1 protein expression was associated with estrogen receptor (P=0.016) and HER2 status (P=0.037). Furthermore, SLC50A1 levels were positively related to unfavorable 3-year outcomes in patients with high-grade breast cancer (HR =1.823, P=0.01), indicating its potential use as an independent prognostic factor. Conclusion: SLC50A1 can be used as a serum-based diagnostic and prognostic biomarker in breast cancer. However, further studies are needed to clarify its potential role as a therapeutic target. Keywords: breast cancer, SLC50A1, biomarker, serum, prognosis Introduction Breast cancer is one of the most common malignancies in women in China and the leading cause of mortality in western countries.1,2 Although biomarkers may provide an effective tool for diagnostic screening and therapeutic targeting in breast cancer, 3 Correspondence: Yu Fan few biomarkers have yet been validated for clinical application. The limitations of Department of Oncology, The Affiliated mammography, ultrasound, and magnetic resonance imaging indicate the need for Hospital of Southwest Medical University, additional, minimally invasive tests.4 Measurement of serum biomarkers constitutes No 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, China a promising tool for detecting and monitoring breast cancer. However, mucin 1 and Tel +86 15283035180 carcinoembryonic antigen levels are currently the only circulating biomarkers recom- Fax +86 08303165396 Email [email protected] mended as supplementary tests for monitoring patients with metastatic breast cancer.3 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11 865–876 865 Dovepress © 2019 Wang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/CMAR.S190591 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Wang et al Dovepress New serum biomarkers for screening and predicting progno- material was immediately snap-frozen in liquid nitrogen. The sis are therefore needed to improve the treatment of patients patients’ characteristics are shown in Table S1. with breast cancer. Sugars are the main source of energy and cells employ Serum samples numerous transporter proteins to introduce sugars through Serum samples from breast cancer patients (n=85) and the plasma membrane. Cancer cells display enhanced sugar cancer-free healthy individuals (n=30) were obtained from the uptake and consumption, and sugar transporters have been Department of Breast Surgery and the Department of Health shown to be deregulated in cancer cells, leading to increased Management of the Affiliated Hospital of Southwest Medical sugar accumulation.5 Three classes of eukaryotic sugar University. All individuals gave written informed consent for transporters have been characterized to date, including the retention and analysis of the samples, and the study was glucose transporters (GLUTs), sodium–glucose symporters approved by the ethics committees of the Affiliated Hospital (SGLTs), and a new class of sugar transporters (SWEETs). of Southwest Medical University (approval no KY2014-037). For example, overexpression of GLUT1 was identified as Peripheral blood was drawn immediately after a definitive a prognostic indicator for cancer,6 while GLUT3 has been diagnosis and before receiving any treatment. The obtained shown to activate oncogenic signaling pathways, including blood samples (5 mL per patient) were centrifuged at 600× EGFR, MEK, and AKT, leading to loss of tissue polarity and g for 5 minutes at room temperature, and the isolated serum increased growth in non-malignant breast cells.7 Understand- (2–3 mL) was aliquoted (1–1.5 mL) and stored at –80°C ing sugar transport also has important therapeutic implica- until use. Clinicopathological variables in the breast cancer tions, such as in limiting access of cancer cells to sugars.8 patients are summarized in Table S2. The new SWEET class of glucose uniporters, SLC50, is represented by a single member in the human genome, Bioinformatics analysis SLC50A1 (RAG1AP1).9 Analysis of a data set including 730 Because of the importance of cell membrane proteins as breast cancer and 82 adjacent normal samples identified new therapeutic targets, we screened for potential novel mem- biomarker candidates for breast cancer development (PTF1A, brane proteins as breast cancer biomarkers using Oncomine RABIF, RAG1AP1, TIMM17A, and LOC148145) and pro- (https://www.oncomine.org/)12 and Genecard (https://www. gression (SERPINE3 and ZNF706).10 However, the value of genecards.org/).13 Based on the GEO dataset (GSE7904 and serum SLC50A1 for predicting the diagnosis and prognosis GSE21422), SLC50A1 mRNA levels were confirmed to be of breast cancer is unclear. In this study, we measured serum increased in breast cancer compared with normal tissues. SLC50A1 levels in patients with breast cancer and normal Furthermore, we analyzed the possible relationship between controls by ELISA and speculated that serum SLC50A1 SLC50A1 and clinical parameters of breast cancer using the might be a useful diagnostic and prognostic biomarker in analytical tool, GOBO (http://co.bmc.lu.se/gobo/).14 breast cancer patients. RNA extraction and reverse Materials and methods transcription-PCR (RT-PCR) Cell lines and clinical specimens Total RNA was isolated from cell lines and cryopreserved Breast cancer cell lines (BT-549, MDA-MB-231, MDA- specimens (20–30 mm3 each) using the standard TRIzol MB-468, MCF7, T-47D, and SK-BR-3) were obtained from (Thermo Fisher Scientific, Waltham, MA, USA) procedure American Type Culture Collection (The Global Bioresource for RNA extraction. Extracted RNA was quantified using Center, ATCC, Manassas, VA, USA) and were maintained a NanoDrop ND2000 spectrophotometer (Thermo Fisher as described previously.11 Twenty paired breast cancer and Scientific). The 260/280 nm ratio was generally between normal adjacent tissues were obtained from patients who 1.6 and 1.9. cDNA was subsequently synthesized using 1 µg underwent surgery at the Department of Breast Surgery, of total RNA with a reverse transcription system (Promega the Affiliated Hospital of Southwest Medical University. Corporation, Fitchburg, WI, USA) and stored at –20°C until All participants provided written informed consent, and the use. Semi-quantitative RT-PCR was performed using cell study was approved by the ethics committee of the Affili- lines, as described previously.15 RT products were amplified ated Hospital of Southwest Medical University (approval using Go-Taq® (Promega Corporation), with 32 cycles for no KY2014-037) and was conducted in accordance with the SLC50A1 and 23 cycles for glyceraldehyde 3-phosphate principles of the Declaration
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