Circulating Plasma miRNA-21 as a Superior Biomarker Compared to CA 15-3: Assessment in Healthy Age Matched Subjects and Different Stage of Breast Cancer Patients
Abstract
BACKGROUND: Carbohydrate antigens 15-3 (CA 15-3) is a conventional tumor marker in breast cancer, with low sensitivity and specificity. MicroRNA (miRNA)-21 showed its stability in circulation and could serve as powerful biomarker. The aim of this study was to evaluate miRNA-21 as breast cancer biomarker compared to CA 15-3 in Indonesian population.
METHODS: Circulating plasma miRNA-21 expression was measured using qRT-PCR in 49 patients at various stages of breast cancer and 16 healthy controls. The relative expression value of miRNA-21 was calculated using 2-ΔΔCt. Meanwhile, CA 15-3 was quantified using electrochemiluminescence immunoassay (ECLIA) methods. The results of miRNA-21 and CA 15-3 plasma circulating expression were compared with controls at each stage and between stages of breast cancer.
RESULTS: CA 15-3 median level in breast cancer group was 1.60 times higher compared to control group (p=0.019), 21.00 m/mL and 13.05 m/mL, respectively. Median miRNA-21 expression in breast cancer group was elevated 4.92 folds compared to control group (p=0.001), 4.43 and 0.90, respectively. There was no significant difference of CA 15-3 level between controls and all stages of breast cancer group. CA 15-3 cut-off value was 15.05 m/mL (p=0.016) with 59.2% sensitivity and 62.5% specificity. Meanwhile, there was a significant difference of miRNA-21 expression between controls and most stages of breast cancer group. Circulating miRNA-21 expression cut-off value was 2.07 (p=0.000) with 91.8% sensitivity and 87.5% specificity.
CONCLUSION: Circulating miRNA-21 expression and CA 15-3 levels were significantly increased in breast cancer group compared to control group. The miRNA-21 expression increased consistently with breast cancer stage progression. miRNA-21 could serve as superior biomarker compared to CA 15-3.
KEYWORDS: biomarker, breast cancer, circulating plasma, liquid biopsy, miRNA-21
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68: 394-424, CrossRef.
Forman D, Ferlay J, Steward BW, Wild CP. The global and regional burden of cancer. In: Stewart BW, Wild CP, editors. World Cancer Report 2014. Geneva: WHO Press; 2014, article.
Nassar FJ, Nasr R, Talhouk R. MicroRNAs as biomarkers for early breast cancer diagnosis, prognosis and therapy prediction. Pharmacol Ther. 2017; 172: 34-49, CrossRef.
Sandya Rani GSB, Bitla A. Breast cancer diagnosis – role of biomarkers. J Clin Sci Res. 2017; 6: 225-36, CrossRef.
Kharkwal S, Sameer A, Mukherjee A. Triple test in carcinoma breast. J Clin Diagnostic Res. 2014; 8: NC09-NC11, CrossRef.
Kahraman M, Röske A, Laufer T, Fehlmann T, Backes C, Kern F, et al. MicroRNA in diagnosis and therapy monitoring of early-stage triple-negative breast cancer. Sci Rep. 2018; 8: 11584, CrossRef.
Heywang-Köbrunner SH, Hacker A, Sedlacek S. Advantages and disadvantages of mammography screening. Breast Care. 2011; 6: 199-207, CrossRef.
Lauro S, Trasatti L, Bordin F, Lanzetta G, Bria E, Gelibter A, et al. Comparison of CEA, MCA, CA 15-3 and CA 27-29 in follow up and monitoring therapeutic response in breast cancer patients. Anticancer Res. 1999; 19: 3511-5, PMID.
Gao J, Zhang Q, Xu J, Guo L, Li X. Clinical significance of serum miR-21 in breast cancer compared with CA153 and CEA. Chin J Cancer Res. 2013; 25: 743-8, CrossRef.
Shao Y, Sun X, He Y, Liu C, Liu H. Elevated levels of serum tumor markers CEA and CA15-3 are prognostic parameters for different molecular subtypes of breast cancer. PLoS One. 2015; 10: e0133830, CrossRef.
Pissaia A, Bernard D, Scatton O, Soubrane O, Conti F, Calmus Y. Significance of serum tumor markers carcinoembryonic antigen, CA 19-9, CA 125, and CA 15-3 in pre-orthotopic liver transplantation evaluation. Transplant Proc. 2009; 41: 682-4, CrossRef.
Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Kerin MJ. MicroRNAs as novel biomarkers for breast cancer. J Oncol. 2009; 2009: 950201, CrossRef.
Pan X, Wang ZX, Wang R. MicroRNA-21: A novel therapeutic target in human cancer. Cancer Biol Ther. 2010; 10: 1224–32, CrossRef.
Mar-Aguilar F, Mendoza-Ramírez JA, Malagón-Santiago I, Espino- Silva PK, Santuario-Facio SK, Ruiz-Flores P, et al. Serum circulating microRNA profiling for identification of potential breast cancer biomarkers. Dis Markers. 2013; 34: 163-9, CrossRef.
Yan LX, Wu QN, Zhang Y, Li YY, Liao DZ, Hou JH, et al. Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivotumor growth. Breast Cancer Res. 2011; 13: R2, CrossRef.
Qian B, Katsaros D, Lu L, Preti M, Durando A, Arisio R, et al. High miR-21 expression in breast cancer associated with poor diseasefree survival in early stage disease and high TGF-β1. Breast Cancer Res Treat. 2009; 117: 131-40, CrossRef.
Fu SW, Chen L, Man YG. miRNA Biomarkers in Breast Cancer Detection and Management. J Cancer. 2011; 2: 116-22, CrossRef.
Suresh K, Chandrashekara S. Sample size estimation and power analysis for clinical research studies. J Hum Reprod Sci. 2012; 5: 7-13, CrossRef.
Uehara M, Kinoshita T, Hojo T, Akashi-Tanaka S, Iwamoto E, Fukutomi T. Long-term prognostic study of carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3) in breast cancer. Int J Clin Oncol. 2008; 13: 447, CrossRef.
Tiberio P, Callari M, Angeloni V, Daidone MG, Appierto V. Challenges in using circulating miRNAs as cancer biomarkers. Biomed Res Int. 2015; 2015: 731479, CrossRef.
Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008; 105: 10513-8, CrossRef.
Mirabelli P, Incoronato M. Usefulness of traditional serum biomarkers for management of breast cancer patients. Biomed Res Int. 2013; 2013: 685641, CrossRef.
Ribas J, Ni X, Castanares M, Liu MM, Esopi D, Yegnasubramanian S, et al. A novel source for miR-21 expression through the alternative polyadenylation of VMP1 gene transcripts. Nucleic Acids Res. 2012; 40: 6821-33, CrossRef.
Feng YH, Tsao CJ. Emerging role of microRNA-21 in cancer (Review). Biomed Reports. 2016; 5: 395-402, CrossRef.
Ma X, Choudhury SN, Hua X, Dai Z, Li Y. Interaction of the oncogenic miR-21 microRNA and the p53 tumor suppressor pathway. Carcinogenesis. 2013; 34: 1216-23, CrossRef.
Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008; 18: 350-9, CrossRef.
Jiang LH, Ge MH, Hou XX, Cao J, Hu SS, Lu XX, et al. miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma. Lab Investig. 2015; 95: 1398-408, CrossRef.
Ibrahim H, Fattah A, Mahmoud NH, Elzoghby DM, Matar MM, Elshaer IMM. Clinical utility of circulating microRNA-21 in breast Cancer. Egypt J Hosp Med. 2018; 71: 2950-5, article.
Badr FM. Potential role of miR-21 in breast cancer diagnosis and therapy. Biotechnol Biomed Eng. 2016; 3: 1068, article.
Toraih EA, Mohammed EA, Farrag S, Ramsis N, Hosny S. Pilot study of serum microRNA-21 as a diagnostic and prognostic biomarker in Egyptian breast cancer Patients. Mol Diagn Ther. 2015; 19: 179-90, CrossRef.
Han JG, Jiang YD, Zhang CH, Yang YM, Pang D, Song YN, et al. A novel panel of serum miR-21/miR-155/miR-365 as a potential diagnostic biomarker for breast cancer. Ann Surg Treat Res. 2017; 92: 55-66, CrossRef.
DOI: https://doi.org/10.18585/inabj.v12i2.1142
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