Serum Carboxypeptidase N1 Serves as a Potential Biomarker Complementing CA15-3 for Breast Cancer

Author(s): Ranliang Cui, Chaomin Wang, Qi Zhao, Yichao Wang*, Yueguo Li*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 17 , 2020


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Abstract:

Background: The incidence and mortality of breast cancer are increasing annually. Breast cancer seriously threatens women's health and quality of life. We aimed to measure the clinical value of CPN1, a new serum marker of breast cancer and to evaluate the efficacy of CPN1 in combination with CA15-3.

Methods: Seventy samples of breast cancer with lymph node metastasis, seventy-three samples of nonmetastatic breast cancer and twenty-five samples of healthy human serum were collected. Serum CA15-3 concentration was determined by Roche Elecsys, and serum CPN1 concentration was determined by ELISA.

Results: In breast cancer patients, serum CPN1 concentration was positively correlated with tumour size, clinical stage and CA15-3 concentration (r = 0.376, P<0.0001). ROC curve analysis showed that the optimal critical concentration of CPN1 for breast cancer diagnosis was 32.8pg/ml. The optimal critical concentration of CPN1 in the diagnosis of metastatic breast cancer was 66.121pg/ml. CPN1 has a greater diagnostic ability for breast cancer (AUCCA15-3=0.702 vs. AUCCPN1=0.886, P<0.0001) and metastatic breast cancer (AUCCA15-3=0.629 vs. AUCCPN1=0.887, P<0.0001) than CA15-3, and the combined detection of CA15-3 and CPN1 can improve the diagnostic efficiency for breast cancer (AUCCA15-3+CPN1=0.916) and for distinguishing between metastatic and non-metastatic breast cancer (AUCCA15-3+CPN1=0.895).

Conclusion: CPN1 can be used as a new tumour marker to diagnose and evaluate the invasion and metastasis of breast cancer. The combined detection of CPN1 and CA15-3 is more accurate and has a certain value in clinical application.

Keywords: Biomarker panel, carboxypeptidase N1, CA15-3, breast cancer, metastasis, clinical application.

[1]
Ming-yan, H.E.; Zhu, B-Q.; Zhong, Y. Analysis of the incidence and mortality trend of breast cancer in Chinese women from 2005 to 2013. Ch. J. Dis. Control Prev., 2019, 23, 10-14.
[2]
Jun, W. Value of combined detection of tumor markers CA15-3, CA125, CEA and HER-2 in the diagnosis of breast. Xiandai Jianyan Yixue Zazhi, 2018, 33, 119-121.
[3]
Chen, W.; Zheng, R.; Baade, P.D.; Zhang, S.; Zeng, H.; Bray, F.; Jemal, A.; Yu, X.Q.; He, J. Cancer statistics in China, 2015. CA Cancer J. Clin., 2016, 66(2), 115-132.
[http://dx.doi.org/10.3322/caac.21338] [PMID: 26808342]
[4]
Lee, J.S.; Park, S.; Park, J.M.; Cho, J.H.; Kim, S.I.; Park, B.W. Elevated levels of preoperative CA 15-3 and CEA serum levels have independently poor prognostic significance in breast cancer. Ann. Oncol., 2013, 24(5), 1225-1231.
[http://dx.doi.org/10.1093/annonc/mds604] [PMID: 23230137]
[5]
Ling, X.U.; Yinhua, L.I.U. International guidelines on breast cancer and Chinese clinical practice. J. of Clin. Surgery, 2019, 27, 181-183.
[6]
Wu, S.G.; He, Z.Y.; Zhou, J.; Sun, J.Y.; Li, F.Y.; Lin, Q.; Guo, L.; Lin, H.X. Serum levels of CEA and CA15-3 in different molecular subtypes and prognostic value in Chinese breast cancer. Breast, 2014, 23(1), 88-93.
[http://dx.doi.org/10.1016/j.breast.2013.11.003] [PMID: 24291374]
[7]
Yao, X.; Song, H.; Yan, J. Progress in screening of breast cancer by mammography combined with altrasonography. J. Ch. Pract. Diagn. Ther., 2019, 33, 400-402.
[8]
Chen, Z.; Le, W.; Lingbin, D. The accuracy of mammography screening for breast cancer: A meta-analysis. Chin. J. Epidemiol., 2016, 37, 1269-1305.
[9]
Tang, S.; Wei, L.; Sun, Y. CA15-3 in breast secretions as a potential molecular marker for diagnosing breast cancer: A meta analysis.PLoS One, 2016, 11, 0-12.
[10]
Braden, A.M.; Stankowski, R.V.; Engel, J.M.; Onitilo, A.A. breast cancer biomarkers: Risk assessment, diagnosis, prognosis, prediction of treatment efficacy and toxicity, and recurrence. Curr. Pharm. Des., 2014, 20, 4879-4898.
[11]
Cai, W.; Cai, Z. The value of common tumor markers detection in clinical application. Ch. Contin. Med. Educat., 2019, 11, 64-66.
[12]
Wen, S.; Feng, Q.; Li, L. Value of three tumor markers detection in the follow-up of breast cancer., 2015, 12, 1356-1357+1360.
[13]
Yan, L.X.; Huang, X.F.; Shao, Q.; Huang, M.Y.; Deng, L.; Wu, Q.L.; Zeng, Y.X.; Shao, J.Y. MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA, 2008, 14(11), 2348-2360.
[http://dx.doi.org/10.1261/rna.1034808] [PMID: 18812439]
[14]
Wallwiener, M.; Hartkopf, A.D.; Riethdorf, S.; Nees, J.; Sprick, M.R.; Schönfisch, B.; Taran, F.A.; Heil, J.; Sohn, C.; Pantel, K.; Trumpp, A.; Schneeweiss, A. The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: A retrospective study in 107 patients. BMC Cancer, 2015, 15, 403.
[http://dx.doi.org/10.1186/s12885-015-1423-6] [PMID: 25972110]
[15]
Iqbal, S.; Vishnubhatla, S.; Raina, V.; Sharma, S.; Gogia, A.; Deo, S.S.; Mathur, S.; Shukla, N.K. Circulating cell-free DNA and its integrity as a prognostic marker for breast cancer. Springerplus, 2015, 4, 265.
[http://dx.doi.org/10.1186/s40064-015-1071-y] [PMID: 26090312]
[16]
Duffy, M.J.; O’Grady, P.; Devaney, D.; O’Siorain, L.; Fennelly, J.J.; Lijnen, H.J. Urokinase-plasminogen activator, a marker for aggressive breast carcinomas. Preliminary report. Cancer, 1988, 62(3), 531-533.
[http://dx.doi.org/10.1002/1097-0142(19880801)62:3<531:AID-CNCR2820620315>3.0.CO;2-B] [PMID: 3134120]
[17]
Qing, Z.; Lin, G. Recent advances in biomarkers of breast cancer. Chem. Life, 2018, 40, 85-90.
[18]
Li, Y.; Li, Y.; Chen, T.; Kuklina, A.S.; Bernard, P.; Esteva, F.J.; Shen, H.; Ferrari, M.; Hu, Y. Circulating proteolytic products of carboxypeptidase N for early detection of breast cancer. Clin. Chem., 2014, 60(1), 233-242.
[http://dx.doi.org/10.1373/clinchem.2013.211953] [PMID: 24146311]
[19]
Cui, R.; Zhang, P.; Li, Y. Role of carboxypeptidase N invasion and migration in breast cancer. Anticancer. Agents Med. Chem., 2016, 16(9), 1198-1202.
[http://dx.doi.org/10.2174/1871520616666160201104939] [PMID: 26860443]
[20]
Handa, T.; Katayama, A.; Yokobori, T.; Yamane, A.; Fujii, T.; Obayashi, S.; Kurozumi, S.; Kawabata-Iwakawa, R.; Gombodorj, N.; Nishiyama, M.; Asao, T.; Shirabe, K.; Kuwano, H.; Oyama, T. Carboxypeptidase A4 accumulation is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer. Int. J. Oncol., 2019, 54(3), 833-844.
[http://dx.doi.org/10.3892/ijo.2019.4675] [PMID: 30628666]
[21]
Sun, L.; Wang, Y.; Yuan, H.; Burnett, J.; Pan, J.; Yang, Z.; Ran, Y.; Myers, I.; Sun, D. CPA4 is a novel diagnostic and prognostic marker for human non-small-cell lung cancer. J. Cancer, 2016, 7(10), 1197-1204.
[http://dx.doi.org/10.7150/jca.15209] [PMID: 27390594]
[22]
Tamura, K.; Yu, J.; Hata, T.; Suenaga, M.; Shindo, K.; Abe, T.; MacGregor-Das, A.; Borges, M.; Wolfgang, C.L.; Weiss, M.J.; He, J.; Canto, M.I.; Petersen, G.M.; Gallinger, S.; Syngal, S.; Brand, R.E.; Rustgi, A.; Olson, S.H.; Stoffel, E.; Cote, M.L.; Zogopoulos, G.; Potash, J.B.; Goes, F.S.; McCombie, R.W.; Zandi, P.P.; Pirooznia, M.; Kramer, M.; Parla, J.; Eshleman, J.R.; Roberts, N.J.; Hruban, R.H.; Klein, A.P.; Goggins, M. Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. Proc. Natl. Acad. Sci. USA, 2018, 115(18), 4767-4772.
[http://dx.doi.org/10.1073/pnas.1720588115] [PMID: 29669919]
[23]
Sun, L.; Cao, J.; Guo, C.; Burnett, J.; Yang, Z.; Ran, Y.; Sun, D. Associations of carboxypeptidase 4 with ALDH1A1 expression and their prognostic value in esophageal squamous cell carcinoma. Dis. Esophagus, 2017, 30(6), 1-5.
[http://dx.doi.org/10.1093/dote/dox011] [PMID: 28475748]
[24]
Thomas, L.N.; Merrimen, J.; Bell, D.G.; Rendon, R.; Goffin, V.; Too, C.K. Carboxypeptidase-D is elevated in prostate cancer and its anti-apoptotic activity is abolished by combined androgen and prolactin receptor targeting. Prostate, 2014, 74(7), 732-742.
[http://dx.doi.org/10.1002/pros.22793] [PMID: 24615730]
[25]
Zhao, X.; Lu, C.; Chu, W.; Zhang, Y.; Zhang, B.; Zeng, Q.; Wang, R.; Li, Z.; Lv, B.; Liu, J. microRNA-214 governs lung cancer growth and metastasis by targeting carboxypeptidase-D. DNA Cell Biol., 2016, 35(11), 715-721.
[http://dx.doi.org/10.1089/dna.2016.3398] [PMID: 27494742]
[26]
Jin, T.; Fu, J.; Feng, X.J.; Wang, S.M.; Huang, X.; Zhu, M.H.; Zhang, S.H. SiRNA-targeted carboxypeptidase D inhibits hepatocellular carcinoma growth. Cell Biol. Int., 2013, 37(9), 929-939.
[http://dx.doi.org/10.1002/cbin.10113] [PMID: 23589395]
[27]
Höring, E.; Harter, P.N.; Seznec, J.; Schittenhelm, J.; Bühring, H.J.; Bhattacharyya, S.; von Hattingen, E.; Zachskorn, C.; Mittelbronn, M.; Naumann, U. The “go or grow” potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress. Acta Neuropathol., 2012, 124(1), 83-97.
[http://dx.doi.org/10.1007/s00401-011-0940-x] [PMID: 22249620]
[28]
Lee, T.K.; Murthy, S.R.; Cawley, N.X.; Dhanvantari, S.; Hewitt, S.M.; Lou, H.; Lau, T.; Ma, S.; Huynh, T.; Wesley, R.A.; Ng, I.O.; Pacak, K.; Poon, R.T.; Loh, Y.P. An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers. J. Clin. Invest., 2011, 121(3), 880-892.
[http://dx.doi.org/10.1172/JCI40433] [PMID: 21285511]
[29]
He, P.; Varticovski, L.; Bowman, E.D.; Fukuoka, J.; Welsh, J.A.; Miura, K.; Jen, J.; Gabrielson, E.; Brambilla, E.; Travis, W.D.; Harris, C.C. Identification of carboxypeptidase E and gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray. Hum. Pathol., 2004, 35(10), 1196-1209.
[http://dx.doi.org/10.1016/j.humpath.2004.06.014] [PMID: 15492986]
[30]
Denis, C.J.; Deiteren, K.; Hendriks, D.; Proost, P.; Lambeir, A.M. Carboxypeptidase M in apoptosis, adipogenesis and cancer. Clin. Chim. Acta, 2013, 415, 306-316.
[http://dx.doi.org/10.1016/j.cca.2012.11.012] [PMID: 23178445]
[31]
Weaver, J.; Downs-Kelly, E.; Goldblum, J.R.; Turner, S.; Kulkarni, S.; Tubbs, R.R.; Rubin, B.P.; Skacel, M. Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms. Mod. Pathol., 2008, 21(8), 943-949.
[http://dx.doi.org/10.1038/modpathol.2008.84] [PMID: 18500263]
[32]
Tsakiris, I.; Soos, G.; Nemes, Z.; Kiss, S.S.; Andras, C.; Szantó, J.; Dezso, B. The presence of carboxypeptidase-M in tumour cells signifies epidermal growth factor receptor expression in lung adenocarcinomas: The coexistence predicts a poor prognosis regardless of EGFR levels. J. Cancer Res. Clin. Oncol., 2008, 134(4), 439-451.
[http://dx.doi.org/10.1007/s00432-007-0304-z] [PMID: 17922141]
[33]
Lu, D.; Yao, Q.; Zhan, C.; Le-Meng, Z.; Liu, H.; Cai, Y.; Tu, C.; Li, X.; Zou, Y.; Zhang, S. MicroRNA-146a promote cell migration and invasion in human colorectal cancer via carboxypeptidase M/src-FAK pathway. Oncotarget, 2017, 8(14), 22674-22684.
[http://dx.doi.org/10.18632/oncotarget.15158] [PMID: 28186967]
[34]
Skidgel, R.A.; Erdös, E.G. Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator. Int. Immunopharmacol., 2007, 7(14), 1888-1899.
[http://dx.doi.org/10.1016/j.intimp.2007.07.014] [PMID: 18039526]
[35]
Leeb-Lundberg, L.M.; Marceau, F.; Müller-Esterl, W.; Pettibone, D.J.; Zuraw, B.L. International union of pharmacology. XLV. Classification of the kinin receptor family: From molecular mechanisms to pathophysiological consequences. Pharmacol. Rev., 2005, 57(1), 27-77.
[http://dx.doi.org/10.1124/pr.57.1.2] [PMID: 15734727]
[36]
Skidgel, R.A. Human carboxypeptidase N: Lysine carboxypeptidase. Methods Enzymol., 1995, 248, 653-663.
[http://dx.doi.org/10.1016/0076-6879(95)48042-0] [PMID: 7674952]
[37]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[38]
Chen, W.; Zheng, R.; Baade, P.D. Cancer statistics in China 2015. CA Cancer Clin., 2016, 66(2), 115-132.
[39]
Leung, L.L.K.; Morser, J. Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity. J. Thromb. Haemost., 2018, 62, 538-546.
[http://dx.doi.org/10.1111/jth.14199] [PMID: 29883024]
[40]
Fan, J.; Tea, M.K.; Yang, C.; Ma, L.; Meng, Q.H.; Hu, T.Y.; Singer, C.F.; Ferrari, M. Profiling of cross-functional peptidases regulated circulating peptides in BRCA1 mutant breast cancer. J. Proteome Res., 2016, 15(5), 1534-1545.
[http://dx.doi.org/10.1021/acs.jproteome.6b00010] [PMID: 27058005]
[41]
Xu, Z.; Payoe, R.; Fahlman, R.P.; Xu, Z. The C-terminal proteolytic fragment of the breast cancer susceptibility type 1 protein (BRCA1) is degraded by the N-end rule pathway. J. Biol. Chem., 2012, 287(10), 7495-7502.
[http://dx.doi.org/10.1074/jbc.M111.301002] [PMID: 22262859]
[42]
Yang, W.W.; Wang, Z.H.; Zhu, Y.; Yang, H.T. E2F6 negatively regulates ultraviolet-induced apoptosis via modulation of BRCA1. Cell Death Differ., 2007, 14(4), 807-817.
[http://dx.doi.org/10.1038/sj.cdd.4402062] [PMID: 17096023]
[43]
Herman-Bachinsky, Y.; Ryoo, H.D.; Ciechanover, A.; Gonen, H. Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways. Cell Death Differ., 2007, 14(4), 861-871.
[http://dx.doi.org/10.1038/sj.cdd.4402079] [PMID: 17205079]
[44]
Jia-Cun, L.I.; Luo, Z.; Hao, Q.L.J.C.T.M. Diagnostic significance of detection of plasma D-dimer and PAI-1 in COPD patients complicated with PTE by ROC curve. China Trop. Med., 2009, 5, 875-950.
[45]
Osterman, A.L.; Grishin, N.V.; Smulevitch, S.V.; Matz, M.V.; Zagnitko, O.P.; Revina, L.P.; Stepanov, V.M. Primary structure of carboxypeptidase T: Delineation of functionally relevant features in Zn-carboxypeptidase family. J. Protein Chem., 1992, 11(5), 561-570.
[http://dx.doi.org/10.1007/BF01025034] [PMID: 1449602]
[46]
Cawley, N.X.; Wetsel, W.C.; Murthy, S.R.; Park, J.J.; Pacak, K.; Loh, Y.P. New roles of carboxypeptidase E in endocrine and neural function and cancer. Endocr. Rev., 2012, 33(2), 216-253.
[http://dx.doi.org/10.1210/er.2011-1039] [PMID: 22402194]
[47]
Liu, A.; Shao, C.; Jin, G.; Liu, R.; Hao, J.; Shao, Z.; Liu, Q.; Hu, X. Downregulation of CPE regulates cell proliferation and chemosensitivity in pancreatic cancer. Tumour Biol., 2014, 35(12), 12459-12465.
[http://dx.doi.org/10.1007/s13277-014-2564-y] [PMID: 25374060]
[48]
Bouchal, P.; Dvořáková, M.; Roumeliotis, T.; Bortlíček, Z.; Ihnatová, I.; Procházková, I.; Ho, J.T.; Maryáš, J.; Imrichová, H.; Budinská, E.; Vyzula, R.; Garbis, S.D.; Vojtěšek, B.; Nenutil, R. Combined proteomics and transcriptomics identifies carboxypeptidase B1 and Nuclear Factor κB (NF-κB) associated proteins as putative biomarkers of metastasis in low grade breast cancer. Mol. Cell. Proteomics, 2015, 14(7), 1814-1830.
[http://dx.doi.org/10.1074/mcp.M114.041335] [PMID: 25903579]
[49]
Yang, H.L.; Thiyagarajan, V.; Shen, P.C.; Mathew, D.C.; Lin, K.Y.; Liao, J.W.; Hseu, Y.C. Anti-EMT properties of CoQ0 attributed to PI3K/AKT/NFKB/MMP-9 signaling pathway through ROS-mediated apoptosis. J. Exp. Clin. Cancer Res., 2019, 38(1), 186.
[http://dx.doi.org/10.1186/s13046-019-1196-x] [PMID: 31068208]
[50]
Ali, O.S.; Shabayek, M.I.; Seleem, M.M.; Abdelaziz, H.G.; Makhlouf, D.O. MicroRNAs 182 and 375 Sera expression as prognostic biochemical markers in breast cancer. Clin. breast cancer, 2018, 18(6), e1373-e1379.
[http://dx.doi.org/10.1016/j.clbc.2018.07.020] [PMID: 30143449]


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VOLUME: 20
ISSUE: 17
Year: 2020
Published on: 03 July, 2020
Page: [2053 - 2065]
Pages: 13
DOI: 10.2174/1871520620666200703191135
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