Serum CA153 as biomarker for cancer and noncancer diseases

Serum CA153 as biomarker for cancer and noncancer diseases

CHAPTER FIFTEEN Serum CA153 as biomarker for cancer and noncancer diseases Xiulian Lia,b, Yan Xuc, Lijuan Zhangb,* a School of Medicine and Pharmacy...

556KB Sizes 0 Downloads 2 Views

CHAPTER FIFTEEN

Serum CA153 as biomarker for cancer and noncancer diseases Xiulian Lia,b, Yan Xuc, Lijuan Zhangb,* a

School of Medicine and Pharmacy, Ocean University of China, Qingdao, China Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China c Department of Nephrology, Affiliated Hospital of Qingdao University, Qingdao, China *Corresponding author: e-mail address: [email protected] b

Contents 1. Introduction 2. Serum CA153 measurement 3. Serum CA153 levels in 30 different types of diseases 3.1 Methods 3.2 Results 4. Discussions and conclusions Acknowledgments Conflicts of interest References

266 267 268 268 269 272 273 273 273

Abstract CA153 was originally discovered as a tumor antigen recognized by two monoclonal antibodies DF3 and 115D8 simultaneously. Subsequent studies showed that DF3 recognizes the core protein of mucin1 (MUC1 or CD227) whereas 115D8 recognizes part of the glycan chains on MUC1. MUC1 is a highly glycosylated transmembrane protein expressed on the mucosal surfaces of epithelial cells in lung, breast, stomach, gallbladder, lymph node, colon, rectum, and pancreas. The increased serum levels of CA153 have been established as a biomarker for breast cancer diagnosis since 1980s. However, it is unknown if elevated serum CA153 levels were also associated with other cancers and noncancer diseases. In current study, a total of 19,789 clinical lab test results of serum CA153 levels from healthy individuals and patients with 30 different types of diseases during the past 5 years were retrieved and analyzed. According to the mean (SD), median, and p ( Log10 p) values calculated, we found that patients suffering lung, breast, ovarian cancers, nephrotic syndrome, type 2 diabetes, endometrial cancer, coronary heart disease, cervical cancer, uremia, and other 12 diseases plus healthy controls >65 years old had significantly (p < 0.05, Log10 p > 1.30) increased median serum CA153 levels compared to that of healthy controls. Moreover, patients with lymphoma had the highest mean and the biggest SD value for serum CA153. Based on these data

Progress in Molecular Biology and Translational Science, Volume 162 ISSN 1877-1173 https://doi.org/10.1016/bs.pmbts.2019.01.005

#

2019 Elsevier Inc. All rights reserved.

265

266

Xiulian Li et al.

and the documented evidence, we proposed that the increased serum CA153 levels might be associated with pathological leakage of the epithelial cell product into the blood circulation in addition to the decreased CA153 clearance rate.

1. Introduction After the hybridoma technology developed by Kohler and Milstein1 becomes a routine tool, breast cancer cells were used to immunize BALB/c mice to generate monoclonal antibodies against cancer cell-associated antigens.2–4 Two such monoclonal antibodies, DF3 and 115D8, were used to develop an immunoassay,5 which is subsequently used to detect a specific cancer antigen named CA15/3, CA15-3, or CA153 in the sera of breast cancer patients.5–16 Further studies showed that the monoclonal antibody DF3 recognizes the core protein of mucin1 (MUC1 or CD227)17 whereas the monoclonal antibody 115D8 recognizes part of the glycan chains on MUC1.18 The DF3 is an IgG1 whereas the 115D8 is an IgG2b-k with the apparent affinities of 5.26  10 9 and 1.84  10 9 M, respectively, to MUC1.18 MUC1 is a heavily glycosylated protein with a molecular weight of approximately 400–450 kDa.19,20 It is a heterodimeric type I transmembrane protein with 200–500 nm glycosylated extracellular domain consisting of many tandem repeating units of 20 amino acids.21 MUC1 is highly expressed on a series of the apical border of epithelial cells that line the respiratory, reproductive, and gastrointestinal tracts not limited to esophagus, stomach, duodenum, pancreas, uterus, prostate, lymph node, and lung, as well as some hematopoietic cells.22 MUC1 is an extensively glycosylated protein enriched in serine and threonine for O-glycan attachments.23 MUC1 is known to be overexpressed in various cancer tissues.24 The most important feature that distinguishes MUC1 made by healthy epithelial cells from that of cancer cells is that O-glycans have very different chain lengths and structures.3 In healthy subjects, O-linked glycans on MUC1 have a linear polylactosamine chain and can be fucosylated.25 However, shorter O-linked glycans are expressed in breast cancer cells, which are called dense Thomsen–Friedenreich (T/TF) antigens or sialylated TF-antigens.26 GalNAc-Gal are usually detected as the last two monosaccharides at the end of O-linked glycan chains.27

Serum CA153 as biomarker for cancer and noncancer diseases

267

While MUC1 is a transmembrane glycoprotein encoded by the MUC1 gene and expressed in almost all epithelial cells based on the information provided in the Human Protein Atlas database, CA153 is a soluble form of MUC1.28 The blood test is the most ideal way for early cancer diagnosis12 because it is noninvasive and the measurement is easy and reproducible. More importantly, the positive results could also be used as the indicators of disease progression and patients’ response to treatment.29 As a result, the increased serum CA153 levels have been used as both diagnostic and prognostic biomarkers for breast cancer patients since 1980s.6,10,11 Even though CA153 is one of the most accepted serum biomarkers utilized for the diagnosis and prognosis of breast cancer,30,31 it is still unclear how the CA153 is accumulated in blood circulation. If the secretion of CA153 into the blood circulation by cancer cells is solely responsible for the increased CA153 serum levels, which should be correlated with the size of the tumors, but it is not always the case due to the high false negative and false positive rate when CA153 is used as a biomarker. Other study suggested that the increased CA153 serum levels could also be the body’s response to cancer or other conditions.32 Indeed, increased serum CA153 levels are observed in patients with other advanced adenocarcinoma including ovarian, pancreatic, gastric, and lung cancers.7,33–37 It is also reported that the increased serum CA153 levels exist in patients with benign diseases such as chronic active hepatitis, liver cirrhosis, sarcoidosis, megaloblastic anemia.38,39 However, the serum CA153 levels in patients suffering different cancer or noncancer diseases have not been systematically studied and compared. Such information should be useful to understand the molecular mechanisms of increased serum CA153 levels. Thus, in current study a total of 19,789 clinical lab test results of serum CA153 levels from healthy individuals and patients with 30 different types of diseases during the past 5 years were retrieved and analyzed.

2. Serum CA153 measurement A number of methods have been developed to measure serum CA153 levels. Enzyme-linked immunosorbent assay (ELISA) is the most common technique used for the detection of serum CA153.40–42 A conventional ELISA protocol for CA153 is to detect antigens reactive with two

268

Xiulian Li et al.

monoclonal antibodies, DF3 and 115D8, in a sandwich assay. When the primary 115D8 monoclonal antibody is immobilized on the solid phase, the antibody binds to the CA153 in the serum. After incubation, the secondary DF3 monoclonal antibody conjugated to an enzyme is transferred to the mixture and the secondary antibody linked to the enzyme acts as a signal generator. More specifically, 115D8 is used as the CA153 capture antibody on the solid phase and DF3 is used as the detecting antibody that binds to the 8 amino acid (Asp-Thr-Arg-Pro-Ala-Pro-Gly-Ser) in the 20 amino acid tandem repeats of MUC1.43,44 In general, ELISA requires less pretreatment procedures of the sample, but the whole process requires a longer incubation time and multiple removal and washing steps. Besides ELISA has lower assay sensitivity in general. To enhance the sensitivity of the assay, a more sensitive and reliable assay detecting serum CA15-3 levels with electrochemical biosensor labeled with magnetic beads has been reported.45 Other studies directed the attention to the aberrant glycosylation of MUC1, a hallmark of cancer progression.46 The glycosylation of CA153 accounts about for 50%–90% of its total molecular weight.23 Changed glycan structures in CA153 for breast cancer have been reported.47 Recently, antibody-lectin sandwich assay detecting glycosylation of CA153 has been developed and the assay appears to better discriminate breast cancer stages I, II A, II B, and III compared to the ELISA.48 Because almost 60% of the proteins in the blood are glycosylated and more than 100 types of lectins are available for purchase,49 the antibodylectin sandwich assay is a more promising assay to identify different glycoforms of CA153 in future.50

3. Serum CA153 levels in 30 different types of diseases 3.1 Methods We have collected the lab data of serum CA153 levels of both healthy individuals and patients with clinically defined various diseases from the clinical laboratory of Affiliated Hospital of Qingdao University during the past 5 years. Each type of disease that has more than 30 independent test results for serum CA53 levels was included in current study. As a result, a total of 19,789 clinical lab results of CA153 from 30 different types of diseases were used in current study. Statistical analysis was performed by using SPSS version 19. Due to nonnormal distribution, Mann–Whitney test was used for statistical analysis. Two-sided test with a 5% significant level (p < 0.05) was

Serum CA153 as biomarker for cancer and noncancer diseases

269

considered as statistically significant. To compare the differences in p values among different types of diseases with that of healthy control, Log p values were calculated and used.

3.2 Results Based on the data collected, the mean (SD), median, and log10 p values of serum CA153 levels for each type of diseases were listed in Table 1. Based on the median values, Log10 p values were calculated. The p value is used in the context of null hypothesis testing in order to quantify the idea of statistical significance of evidence. In essence, the statistical significance is assumed valid when the p values are far apart from that of control values. Statistical significance is defined when p < 0.05 or Log10 p > 1.30. The mean serum CA153 value is 8.73 U/mL in healthy controls. Therefore, when log10 p value is >1.30 between the diseases and the healthy controls, the differences are significant. The data in Table 1 showed that 27/30 diseases in addition to healthy elderlies (>65 years old) had their median values higher than that of healthy controls. In contrast, patients with pancreatitis, gastritis, and acute myocardial infarction had their median values lower than that of healthy controls, but without the statistical significance ( Log10 p values <1.30). The following diseases had the highest mean values in a descending order: lymphoma (61.49), ovarian cancer (23.67), lung cancer (18.43), breast lump (17.06), nephrotic syndrome (16.43), and postbreast surgery (14.38). The following diseases had the highest SD values: lymphoma (37.16), breast lump (25.11), ovarian cancer (24.93), postbreast surgery (23.70), and cerebral arteriosclerosis (12.10). To make the data more intuitive, scatter diagram of serum CA153 levels in the 30 diseases in comparison to the healthy controls was plotted with lower quartile (25%), median (50%), and upper quartile (75%) marked and showed in Fig. 1. Patients with nephrotic syndrome had the highest median value followed by patients with ovarian cancer, lung cancer, diabetic nephropathy, lymphoma, and cerebral arteriosclerosis whereas patients suffering acute myocardial infarction, gastritis, and pancreatitis had the lowest median values. The Log10 p values were further plotted and showed in Fig. 2. The highest Log10 p values mean the highest difference in the patients as a group compared to the healthy controls as another group. According to the Log10 p values, the increased serum CA153 levels worked best as biomarkers for patients with lung cancer, breast cancer, ovarian cancer, nephrotic syndrome, and type 2 diabetes among other diseases (Table 1).

270

Xiulian Li et al.

Table 1 The mean, median, and Log10 p values of serum CA153 levels (U/mL) for healthy controls and patients with cancer and noncancer diseases. CA153 # of Tests Mean (SD) Median 2Log10 p value

Nephrotic syndrome

127

16.43 (7.94)

14.47

31.75

Ovarian cancer

328

23.67 (24.93) 14.20

54.27

Lung cancer

650

18.43 (18.31) 12.24

81.97

Diabetic nephropathy

45

12.84 (5.85)

11.85

5.04

Lymphoma

30

37.16 (61.49) 11.76

4.27

Cerebral arteriosclerosis

37

13.46 (12.10) 11.07

1.58

Nephritis

96

11.86 (6.02)

10.87

4.22

Azotemia

36

12.37 (7.88)

10.75

1.70

Anemia

85

12.25 (6.48)

10.55

3.96

250

11.75 (5.02)

10.39

12.21

17.06 (25.11) 10.27

3.04

Endometrial cancer Breast lumps

44

Rectum cancer

186

11.51 (5.70)

10.26

6.19

Uremia

144

11.43 (4.43)

10.23

7.30

Osteoporosis

54

10.83 (4.40)

10.14

1.54

Cirrhosis

36

12.05 (5.96)

10.06

2.24

256

10.81 (4.21)

9.94

5.58

7117

11.74 (6.57)

9.87

72.69

45

11.01 (4.65)

9.83

1.82

Colon cancer

188

12.40 (8.28)

9.79

6.32

Cervical Cancer

477

11.32 (6.17)

9.77

7.96

Type 2 diabetes mellitus

1536

10.75 (4.54)

9.73

15.09

Chronic obstructive PD

42

11.64 (5.70)

9.65

1.56

Coronary heart disease

929

10.65 (4.43)

9.50

9.79

Cerebral ischemia

126

9.78 (3.38)

9.36

0.77

Postbreast surgery

57

14.38 (23.70)

9.21

1.46

Acute cerebral infarction

349

10.38 (4.75)

9.17

1.44

Gastric cancer

225

11.10 (7.60)

9.06

1.08

Cerebrovascular disease

456

9.88 (4.07)

8.84

0.65

Healthy controls >65 years old Breast cancer Intracranial hemorrhage

271

Serum CA153 as biomarker for cancer and noncancer diseases

Table 1 The mean, median, and Log10 p values of serum CA153 levels (U/mL) for healthy controls and patients with cancer and noncancer diseases.—cont’d CA153 # of Tests Mean (SD) Median 2Log10 p value

Healthy controls Pancreatitis Gastritis Acute myocardial infarction

5848

9.66 (3.77)

8.73

0.00

42

9.36 (3.49)

8.72

0.44

135

9.57 (4.02)

8.59

0.58

69

10.64 (6.57)

8.54

0.41

230 100

U/mL

30 25 20 15 10 5 N ep hr ot ic O sy va nd ria ro D ia n m be Lu ca e tic ng nc ne ca er C er ph nc eb ra L rop er l a y at rt mp hy er h io om sc l a N ero ep sis A hrit En zo is te do m A mia et ne ria m Br l c ia a R eas nc e ec t tu lum r H m ea ca ps lth n y O Ur cer co st em nt eo i ro po a ls > C ros 65 irr is In h tr ac B yea os ra re rs is ni as o al t ld he can m C or cer Ty pe C olo rha n C 2 d erv ca ge hr i ic o a a nc C nic bete l ca er or o s n on bs m cer ar tru ell y c it C he tiv us er ar e eb t P A P cu o ra dis D l te stb is ea ce re ch se re as em br t s ia C al ur er eb G inf ger ro as ar y va tri cti sc c on H ula can ea r d ce lth is r A y ea cu s c te Pa ont e m nc ro yo re ls ca rd G atit ia a is l i str nf it ar is ct io n

0

Fig. 1 Serum CA153 levels in 30 different types of diseases. The data were sorted in a descending order of the median values. Serum CA153 levels for each type of disease with lower quartile (25%), median (50%), and upper quartile (75%) ranges were marked in red.

Fig. 2 Log10 p values of CA153 in 30 different types of diseases compared to that of healthy controls. The different shades of red colors were used in the plot to indicate the increased Log10 p values in different types of diseases compared to that of healthy controls.

272

Xiulian Li et al.

4. Discussions and conclusions Increased serum CA153 levels have been used as breast cancer biomarker since 1980s. However, based on data obtained from the serum CA153 levels from 13,941 patients with 30 clinically defined diseases as well as serum CA153 levels from 5848 healthy individuals (Table 1), our results showed that increased serum CA153 levels were associated with many different types of diseases: (1) the median serum CA153 levels in patients with 24 diseases were significantly increased ( Log10 p > 1.30) compared to that in healthy controls (Table 1); (2) patients with lymphomas had the highest mean serum CA153 levels and the highest SD value among the 30 diseases (Table 1); (3) based on the Log10 p values, the serum CA153 levels worked best as biomarkers for patients with lung cancer, breast cancer, ovarian cancer, nephrotic syndrome, type 2 diabetes among many other cancers and noncancer diseases (Table 1 and Fig. 2). Therefore, the increased serum CA153 levels were not specifically associated with breast cancer in the measures of the mean (SD), median, or log10 p values of our retrospective studies (Table 1 and Figs. 1 and 2). Mucins are heavily O-glycosylated proteins that play an essential role in forming protective mucous barriers on epithelial surfaces. MUC1 belongs to the mucin family and is a membrane-bound glycoprotein expressed on the apical surface of epithelial cells. MUC1 lines the respiratory, reproductive, and gastrointestinal tracts not limited to esophagus, stomach, duodenum, pancreas, uterus, prostate, lymph node, and lung, as well as some hematopoietic cells.22 MUC1 is proteolytically cleaved into alpha and beta subunits that form a heterodimeric complex. The N-terminal alpha subunit functions in cell-adhesion and the C-terminal beta subunit is involved in cell signaling. Overexpression, aberrant intracellular localization, and changes in glycosylation of MUC1 have been associated with carcinomas. CA153 is a proteolytically cleaved soluble form of MUC1. Our data showed that increased serum CA153 levels were associated not only with different types of cancers but also with noncancer diseases (Table 1 and Figs. 1 and 2). Since MUC1 is a common glycoprotein associated with epithelial and changes in glycosylation are common features of cancer cells and in diseases, it was not surprising that increased serum CA153 levels were not solely associated with breast cancer. Indeed, our data supported the decision of the American Society of Clinical Oncology, who does not recommend the use of the serum CA153 levels for screening and monitoring treatment effects of breast cancer.32

Serum CA153 as biomarker for cancer and noncancer diseases

273

The data presented in our current study indicated that the increased serum CA153 levels could serve as potential serum biomarker for at least 24 different types of human diseases based on the Log10 p values shown in Table 1 and Fig. 2. It was comprehensible that patients with different types of cancers were associated with the increased serum CA153 levels due to the overexpression of MUC1. In the absence of cancer cells, how were the patients suffering the noncancer diseases, such as type 2 diabetes, nephrotic syndrome, cerebral arteriosclerosis, nephritis, anemia, and many others (Fig. 1), associated with the increased serum CA153 levels? Why patients suffering acute myocardial infarction had the lowest median serum CA153 level among the 30 diseases, but a few acute myocardial infarction patients still had extremely high serum CA153 levels (Fig. 1)? Were serum CA153 levels dynamically regulated? What were the molecular mechanisms responsible for such regulation? So far, our data raised more questions than answers. Based on these facts and the documented evidence, we could propose that the increased serum CA153 levels might be associated with pathological leakages of the epithelial cell product, such as CA153, into the blood circulation. Increased serum CA153 levels might also be associated with decreased CA153 clearance in the blood circulation due to system incompetence, which was supported by the observation that healthy controls >65 years old had significantly (p < 0.05, Log10 p > 1.30) increased median serum CA153 levels compared to that of healthy controls (Table 1). In conclusion, finding answers to above questions in future research should make CA153 useful again as a serum biomarker in guiding personalized diagnosis and care for patients with different types of diseases or a patient at specific stage of the disease development.

Acknowledgments This research was supported by the Natural Science Foundation of China (Grant 81672585), Key Technology Fund of Shandong Province (Grant 2016ZDJS07A07), the Taishan Scholar Fellowship, and the “Double First Class fund” of Shandong Province in China to L.Z.

Conflicts of interest The authors declare no conflict of interest.

References 1. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–497. 2. Kufe D, Inghirami G, Abe M, Hayes D, Justi-Wheeler H, Schlom J. Differential reactivity of a novel monoclonal antibody (DF3) with human malignant versus benign breast tumors. Hybridoma. 1984;3(3):223–232.

274

Xiulian Li et al.

3. Springer GF. T and Tn, general carcinoma autoantigens. Science. 1984;224(4654): 1198–1206. 4. Szpak CA, Johnston WW, Lottich SC, Kufe D, Thor A, Schlom J. Patterns of reactivity of four novel monoclonal antibodies (B72.3, DF3, B1.1 and B6.2) with cells in human malignant and benign effusions. Acta Cytol. 1984;28(4):356–367. 5. Tondini C, Hayes DF, Gelman R, Henderson IC, Kufe DW. Comparison of CA15-3 and carcinoembryonic antigen in monitoring the clinical course of patients with metastatic breast cancer. Cancer Res. 1988;48(14):4107–4112. 6. Gang Y, Adachi I, Okhura H, Yamomoto H, Mizuguchi Y, Abe K. CA15-3 is present as a novel tumour marker in the sera of patients with breast cancer and other malignancies. Gan To Kagaku Ryoho. 1985;12:2379–2386. 7. Hayes DF, Zurawski VJ, Kufe DW. Comparison of circulating CA15-3 and carcinoembryonic antigen levels in patients with breast cancer. J Clin Oncol. 1986;4(10):1542–1550. 8. Sacks NP, Stacker SA, Thompson CH, et al. Comparison of mammary serum antigen (MSA) and CA15-3 levels in the serum of patients with breast cancer. Br J Cancer. 1987;56(6):820–824. 9. Colomer R, Ruibal A, Genolla J, et al. Circulating CA 15-3 levels in the postsurgical follow-up of breast cancer patients and in non-malignant diseases. Breast Cancer Res Treat 1989;13(2):123–133. 10. Kerin MJ, McAnena OJ, O’Malley VP, Grimes H, Given HF. CA15-3: its relationship to clinical stage and progression to metastatic disease in breast cancer. Br J Surg. 1989;76(8):838–839. 11. Gion M, Mione R, Nascimben O, et al. The tumour associated antigen CA15.3 in primary breast cancer. Evaluation of 667 cases. Br J Cancer. 1991;63(5):809–813. 12. Safi F, Kohler I, Rottinger E, Beger H. The value of the tumor marker CA 15-3 in diagnosing and monitoring breast cancer. A comparative study with carcinoembryonic antigen. Cancer. 1991;68(3):574–582. 13. Daly L, Ferguson J, Cram Jr GP, et al. Comparison of a novel assay for breast cancer mucin to CA15-3 and carcinoembryonic antigen. J Clin Oncol. 1992;10(7):1057–1065. 14. O’Hanlon DM, Kerin MJ, Kent PJ, et al. A prospective evaluation of CA15-3 in stage I carcinoma of the breast. J Am Coll Surg. 1995;180(2):210–212. 15. Tomlinson IP, Whyman A, Barrett JA, Kremer JK. Tumour marker CA15-3: possible uses in the routine management of breast cancer. Eur J Cancer. 1995;31A(6):899–902. 16. Gion M, Mione R, Leon AE, Dittadi R. Comparison of the diagnostic accuracy of CA27.29 and CA15.3 in primary breast cancer. Clin Chem. 1999;45(5):630–637. 17. Abe M, Kufe D. Structural analysis of the DF3 human breast carcinoma-associated protein. Cancer Res. 1989;49(11):2834–2839. 18. Dai J, Allard WJ, Davis G, Yeung KK. Effect of desialylation on binding, affinity, and specificity of 56 monoclonal antibodies against MUC1 mucin. Tumour Biol. 1998;19(Suppl 1):100–110. 19. Sekine H, Ohno T, Kufe DW. Purification and characterization of a high molecular weight glycoprotein detectable in human milk and breast carcinomas. J Immunol. 1985;135(5):3610–3615. 20. Hilkens J, Buijs F, Ligtenberg M. Complexity of MAM-6, an epithelial sialomucin associated with carcinomas. Cancer Res. 1989;49(4):786–793. 21. Engelstaedter V, Heublein S, Schumacher AL, et al. Mucin-1 and its relation to grade, stage and survival in ovarian carcinoma patients. BMC Cancer. 2012;12(1):600. 22. Riva K, Galit H, Smorodinsky NI, Shapira MY, Lior C. Cell surface-associated antiMUC1-derived signal peptide antibodies: implications for cancer diagnostics and therapy. PLoS One. 2014;9(1): e85400.

Serum CA153 as biomarker for cancer and noncancer diseases

275

23. Sritama N, Pinku M. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014;20(6):332–342. 24. Lau SK, Weiss LM, Chu PG. Differential expression of MUC1, MUC2, and MUC5AC in carcinomas of various sites: an immunohistochemical study. Am J Clin Pathol. 2004;122(1):61–69. 25. Hanisch FG, Uhlenbruck G, Peter-Katalinic J, Egge H, Dabrowski J, Dabrowski U. Structures of neutral O-linked polylactosaminoglycans on human skim milk mucins. A novel type of linearly extended poly-N-acetyllactosamine backbones with Gal beta(1-4)GlcNAc beta(1-6) repeating units. J Biol Chem. 1989;264(2):872–883. 26. Brockhausen I. Pathways of O -glycan biosynthesis in cancer cells. Biochim Biophys Acta. 1999;1473(1):67–95. 27. Ola B, Deanna B, Brian B, et al. Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis. Breast Cancer Res. 2011;13(2):1–16. 28. Darwish IA, Wani TA, Khalil NY, Blake DA. Novel automated flow-based immunosensor for real-time measurement of the breast cancer biomarker CA15-3 in serum. Talanta. 2012;97:499–504. 29. Ghosh I, Bhattacharjee D, Chakrabarti G, Dasgupta A, Dey SK. Diagnostic role of tumour markers CEA, CA15-3, CA19-9 and CA125 in lung cancer. Indian J Clin Biochem. 2013;28(1):24–29. 30. Koepke JA. Molecular marker test standardization. Cancer. 1992;69(S6):1578–1581. 31. Nishimura R, Nagao K, Miyayama H, et al. Elevated serum CA15-3 levels correlate with positive estrogen receptor and initial favorable outcome in patients who died from recurrent breast cancer. Breast Cancer. 2003;10(3):220–227. 32. Harris L, Fritsche H, Mennel R, et al. American society of clinical oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287–5312. 33. Shimokata K, Totani Y, Nakanishi K, et al. Diagnostic value of cancer antigen 15-3 (CA15-3) detected by monoclonal antibodies (115D8 and DF3) in exudative pleural effusions. Eur Respir J. 1988;1(4):341–344. 34. Yasui S, Ando I, Kukita A, Hino H, Ohara K. DF3 (CA15-3) antibody as a marker of cutaneous adnexal tumors. Acta Derm Venereol. 1994;74(2):98–100. 35. Hogendorf P, Skulimowski A, Durczynski A, et al. A panel of CA19-9, Ca125, and Ca15-3 as the enhanced test for the differential diagnosis of the pancreatic lesion. Dis Markers. 2017;2017:8629712. 36. Chen C, Chen Q, Zhao Q, Liu M, Guo J. Value of combined detection of serum CEA, CA72-4, CA19-9, CA15-3 and CA12-5 in the diagnosis of gastric cancer. Ann Clin Lab Sci. 2017;47(3):260–263. 37. Yedema C, Massuger L, Hilgers J, et al. Pre-operative discrimination between benign and malignant ovarian tumors using a combination of CA125 and CA15.3 serum assays. Int J Cancer Suppl. 1988;3:61–67. 38. Duffy MJ, Evoy D, Mcdermott EW. CA 15-3: uses and limitation as a biomarker for breast cancer. Clin Chim Acta. 2010;411(23):1869–1874. 39. Ghnassia JP, Rodier JF, Eber M. Elevation of CA15-3 caused by a benign tumour. Lancet Oncol. 2001;2(2):102. 40. Adriano A, Federico A, Arben MI. Enhanced gold nanoparticle based ELISA for a breast cancer biomarker. Anal Chem. 2010;82(3):1151–1156. 41. Self CH, Cook DB. Advances in immunoassay technology. Curr Opin Biotechnol. 1996;7(1):60–65. 42. Porstmann T, Kiessig ST. Enzyme immunoassay techniques. An overview. J Immunol Methods. 1992;150(1–2):5–21.

276

Xiulian Li et al.

43. Price MR, Rye PD, Petrakou E, et al. Summary report on the ISOBM TD-4 workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. San Diego, Calif., November 17–23, 1996. Tumor Biol. 1998;19(1):1–20. 44. van Kamp GJ, Bon GG, Verstraeten RA. Multicenter evaluation of the Abbott IMx CA 15-3 assay. Clin Chem. 1996;42(1):28–33. 45. Akbari Nakhjavani S, Khalilzadeh B, Samadi Pakchin P, Saber R, Ghahremani MH, Omidi Y. A highly sensitive and reliable detection of CA15-3 in patient plasma with electrochemical biosensor labeled with magnetic beads. Biosens Bioelectron. 2018;122: 8–15. 46. Munkley J, Elliott DJ. Hallmarks of glycosylation in cancer. Oncotarget. 2016;7(23): 35478–35489. 47. Lavrsen K, Mandel, et al. Aberrantly glycosylated MUC1 is expressed on the surface of breast cancer cells and a target for antibody-dependent cell-mediated cytotoxicity. Glycoconj J. 2013;30(3):227–236. 48. Choi JW, Moon BI, Lee JW, Kim HJ, Jin Y, Kim HJ. Use of CA15-3 for screening breast cancer: an antibody-lectin sandwich assay for detecting glycosylation of CA15-3 in sera. Oncol Rep. 2018;40(1):145–154. 49. Nathan S, Halina L. History of lectins: from hemagglutinins to biological recognition molecules. Glycobiology. 2004;14(11):53R. 50. Choi JW, Moon BI, Lee JW, Kim HJ, Jin Y, Kim HJ. Use of CA153 for screening breast cancer: an antibody-lectin sandwich assay for detecting glycosylation of CA153 in sera. Oncol Rep. 2018;40(1):145–154.