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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 2  |  Page : 367-370

Serum butyrylcholinesterase and zinc in breast cancer


1 Department of Biochemistry, Kasturba Medical College Manipal, Manipal University, Manipal, Karnataka, India
2 Department of Surgical Oncology, Kasturba Medical College Manipal, Manipal University, Manipal, Karnataka, India
3 Department of Radio Therapy, Kasturba Medical College Manipal, Manipal University, Manipal, Karnataka, India

Date of Web Publication23-Jun-2017

Correspondence Address:
Krishnananda Prabhu
Professor and Head, Department of Biochemistry, Kasturba Medical College Manipal, Manipal University, Manipal, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.165869

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 > Abstract 

Context: Even though, a large number of serological, molecular markers have been proposed for breast cancer screening, most of them lack specificity, sensitivity, prognostic value, and cost effectiveness. Butyrylcholinesterase (BChE) and its genes are aberrantly expressed in a variety of human cancers. It has-been linked to tumorigenesis, cell proliferation, and cell differentiation. Zinc (Zn) is a cofactor for superoxide dismutase, an enzyme that protects cellular components against free radical-induced damage and carcinogenesis. Therefore, the aim of present study was to estimate and compare serum BChE and serum Zn levels in healthy controls and biopsy proven breast cancer patients before definitive therapy.
Aims: To estimate and compare serum BChE and serum Zn levels in healthy controls and biopsy proven breast cancer patients before definitive therapy.
Settings and Design: Serum BChE and Zn were estimated in 46 newly diagnosed (preoperative) female patients with breast cancer and 50 healthy female volunteers.
Subjects and Methods: Serum BChE and Zn were estimated by spectrophotometric method.
Statistical Analysis Used: Data was expressed as median and inter quartile range. Comparisons between different stages of cancer were done using Kruskal–Wallis test.
Results: There was a significant increase in serum BChE and Zn in breast cancer patients compared to controls (P < 0.001). Serum BChE showed a significant increase and Zn was significantly decreased in different stages of breast cancer.
Conclusions: Both BChE and Zn are inexpensive and can easily be analyzed and may play a role in the management of breast cancer.

Keywords: Breast cancer, butyrylcholinesterase, zinc


How to cite this article:
Kumar R, Razab S, Prabhu K, Ray S, Prakash B. Serum butyrylcholinesterase and zinc in breast cancer. J Can Res Ther 2017;13:367-70

How to cite this URL:
Kumar R, Razab S, Prabhu K, Ray S, Prakash B. Serum butyrylcholinesterase and zinc in breast cancer. J Can Res Ther [serial online] 2017 [cited 2019 Nov 13];13:367-70. Available from: http://www.cancerjournal.net/text.asp?2017/13/2/367/165869


 > Introduction Top


Breast cancer is most common cancer among women worldwide and is the main cause of cancer-related mortality.[1] Its early diagnosis and treatment can significantly reduce the morbidity and mortality. A large number of serological, molecular markers such as cancer antigen 15-3, cancer antigen 27–29, and carcinoembryonic antigen have been proposed for breast cancer screening but most lack specificity, sensitivity, prognostic value, and cost effectiveness.[2],[3] So, there is a need to develop a simple and cost-effective biochemical marker for diagnosis/screening of breast cancer.

Cholinesterase is an enzyme which hydrolyses acetylcholine. Two types of cholinesterase with different biochemical properties have been identified in humans-true cholinesterase and pseudocholinesterase (butyrylcholinesterase [BChE]). True cholinesterase is found in the central nervous system, muscles and in erythrocytes. BChE is an alpha-glycoprotein found in the central and peripheral nervous system, in most tissues, and in the liver. BChE has a half-life of about 12 days.[4],[5] Increased activity of this enzyme has been reported in obesity, diabetes, uremia, hyperthyroidism, and in hyperlipidemic subjects.[6],[7] Studies have shown that BChE genes are aberrantly expressed in a variety of human cancers. Serum BChE has been linked to tumorigenesis, cell proliferation and cell differentiation.[8],[9],[10],[11] BChE has been used as a biochemical marker in the management of head, neck, oral cell squamous carcinoma, and cervical cancers.[12]

Zinc (Zn) acts as a cofactor for enzyme superoxide dismutase. As this enzyme is involved in the protection of cellular components against free radical-induced damage and carcinogenesis,[13] Zn can act as cellular growth protector, including the growth of neoplastic cells.[14] Zn stabilizes DNA and RNA polymerase, inhibits phosphodiesterase and activates adenylate cyclase suggesting its importance oncogenesis. Based on animal models, Zn deficiency has also been linked to initiation and malignant transformation in different cancers.[15],[16],[17],[18] Further, Bhanumathy et al., demonstrated that enzyme BChE has two Zn binding sites and Zn is an effective inhibitor of enzyme BChE under normal physiological conditions indicating a possible synergy between these two in preventing or promoting cancer.[19],[20]

Therefore, the aim of present study was to estimate and compare serum BChE and serum Zn levels in healthy controls and biopsy proven breast cancer patients before definitive therapy.


 > Subjects and Methods Top


Subjects

Permission from Institutional Ethics Committee and consent from participants were obtained before carrying out this study. This prospective cross-sectional study included 50 female patients who were newly diagnosed (preoperative) with breast cancer. All patients were nonsmokers, nonalcoholic, and were not on any long-term medications. None of the patients had any other serious medical or surgical illness. Controls consisted of 50 healthy females randomly selected from a group of healthy nonsmoking volunteers with no history of previous disease, drug, or alcohol consumption.

Blood collection

Blood samples were collected from all the subjects into empty red capped vacutainer and immediately stored on ice at 4°C.[21] The serum was then separated and stored at −20°C until use. Serum was used for the measurement of BChE and Zn.

Estimation of serum butyrylcholinesterase

Acetylthiocholine was hydrolyzed by BChE to corresponding fatty acid and thiocholine. The rate of formation of thiocholine was monitored by continuous reaction of thiol group with 5,5'-dithio-bis-(nitrobenzoic acid) to form a yellow anion that was measured spectrophotometrically at 410 nm.[18] Enzyme activity was calculated by molar absorption coefficient of the product of chemical reaction, 5-thio-2-nitrobenzoate (1.36 × mmol −1 × min −1 × cm −1).

Estimation of zinc

Principle

Zn in an alkaline medium reacts with nitro-phospho- adenosine phosphosulfate (PAPS) to form a purple colored complex. The intensity of the complex formed is directly proportional to the amount of Zn present in the sample.[22],[23],[24]

Zn + nitro-PAPS purple colored complex

Statistical analysis

The data analysis was done by using SPSS statistic analyzer software Version 15.0 (Lenience-SPSS Bangalore, Southeast Asia) data was expressed as median and inter quartile range. Comparisons between different stages of cancer were done using Kruskal–Wallis test. Pairwise comparisons were done using Mann–Whitney U-test with Bonferroni correction for type I error.


 > Results Top


There was a significant increase in serum levels of BChE and Zn in breast cancer patients compared to controls (P < 0.001) [Table 1].
Table 1: Comparison of serum BChE and Zn levels in controls and breast cancer patients

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Serum levels of BChE showed a significant increase between different stages of breast cancer except between stages 2 and 3 [Table 2]. Serum Zn was also significantly higher in stages 3 and 4 when compared with that of stage 2 (P < 0.001) [Table 3].
Table 2: Comparison of serum BChE in different stages of breast cancer

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Table 3: Comparison of serum Zn in different stages of breast cancer

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 > Discussion Top


In the present study serum levels of BChE and Zn were compared between breast cancer patients and healthy controls. Our study showed the median value of serum BChE was significantly increased in breast cancer patients as compared to that of controls (P< 0.001) [Table 1]. There was also a significant increase in BChE values with the advancement of cancer [Table 2] supporting its role tumorigenesis as mentioned in previous studies.[25] Similar studies have shown abnormal expression of both BChE and acetylcholinesterase, andin vivo amplification of their genes in intracranial neoplasms such as meningioma, glioma and acoustic neuromas, lung cancers, megakaryocytopoietic disorders, leukemia, and ovarian tumors.[26] BChE can affect cell proliferation by virtue of its antiapoptotic effects and by its ability to enhance anchorage independent cell growth which helps in cancer metastasis.[26]

It was also observed that median level of serum Zn was significantly lower in breast cancer patient than that of controls, and its levels were significantly decreased in stage 2 to stage 4 of cancer. These observation were accordance with Kuo et al., and other studies.[15],[27],[28] They had concluded that Zn is required for the structural stability of Zn finger proteins (Zfps). These Zfp plays an important role in transcriptional regulation of cellular metabolic network, interacting with Zn binding domains such as Zn fingers, RING fingers, and LIM domains, which is critical for DNA synthesis, RNA transcription, cell division, and cell activation. The regulation of cell proliferation by Zn can occur at different levels including the requirement of Zn for the activity of enzymes involved in DNA synthesis (i.e. deoxythymidine kinase) and the modulation of regulatory signals directly, as well as indirectly, through its effects on the hormonal regulation of cell division. So, deficiency/decrease in Zn levels might have contributed to the dysregulation of these above pathways leading to carcinogenesis.

Limitations

The findings of our study cannot be generalized as the sample size is very small. Also, serum BChE and Zn are not specific markers for breast cancer and their activity may alter in cancer of other tissues.


 > Conclusions Top


As we have observed a significant increase in BChE and a significant decrease in Zn in breast cancer patients, they may have a role in the management of breast cancer. Further studies in a larger cohort can provide a definitive data about the prognostic role of these markers.

Financial support and sponsorship

This study was supported by Kasturba Medical College, Manipal Registration Number-ACCT/PGGRANT/2014-15.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Hortobagyi GN, de la Garza Salazar J, Pritchard K, Amadori D, Haidinger R, Hudis CA, et al. The global breast cancer burden: Variations in epidemiology and survival. Clin Breast Cancer 2005;6:391-401.  Back to cited text no. 1
    
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Duffy MJ, Shering S, Sherry F, McDermott E, O'Higgins N. CA 15-3: A prognostic marker in breast cancer. Int J Biol Markers 2000;15:330-3.  Back to cited text no. 2
    
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Gion M, Mione R, Leon AE, Lüftner D, Molina R, Possinger K, et al. CA27.29: A valuable marker for breast cancer management. A confirmatory multicentric study on 603 cases. Eur J Cancer 2001;37:355-63.  Back to cited text no. 3
    
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Ostergaard D, Viby-Mogensen J, Hanel HK, Skovgaard LT. Half-life of plasma cholinesterase. Acta Anaesthesiol Scand 1988;32:266-9.  Back to cited text no. 4
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Pan Y, Muzyka JL, Zhan CG. Model of human butyrylcholinesterase tetramer by homology modeling and dynamics simulation. J Phys Chem B 2009;113:6543-52.  Back to cited text no. 5
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Paes AM, Carniatto SR, Francisco FA, Brito NA, Mathias PC. Acetylcholinesterase activity changes on visceral organs of VMH lesion-induced obese rats. Int J Neurosci 2006;116:1295-302.  Back to cited text no. 6
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Cucuianu M, Nistor T, Hâncu N, Orbai P, Muscurel C, Stoian I. Serum cholinesterase activity correlates with serum insulin, C-peptide and free fatty acids levels in patients with type 2 diabetes. Rom J Intern Med 2002;40:43-51.  Back to cited text no. 7
    
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Small DH, Michaelson S, Sberna G. Non-classical actions of cholinesterases: Role in cellular differentiation, tumorigenesis and Alzheimer's disease. Neurochem Int 1996;28:453-83.  Back to cited text no. 8
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Zakut H, Ehrlich G, Ayalon A, Prody CA, Malinger G, Seidman S, et al. Acetylcholinesterase and butyrylcholinesterase genes coamplify in primary ovarian carcinomas. J Clin Invest 1990;86:900-8.  Back to cited text no. 9
    
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Chatonnet A, Lockridge O. Comparison of butyrylcholinesterase and acetylcholinesterase. Biochem J 1989;260:625-34.  Back to cited text no. 10
    
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Bradamante V, Smigovec E, Bukovic D, Geber J, Matanic D. Plasma cholinesterase activity in patients with uterine cervical cancer during radiotherapy. Coll Antropol 2000;24:373-80.  Back to cited text no. 11
    
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Cerutti PA. Oxidant stress and carcinogenesis. Eur J Clin Invest 1991;21:1-5.  Back to cited text no. 13
    
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Fong LY, Lau KM, Huebner K, Magee PN. Induction of esophageal tumors in zinc-deficient rats by single low doses of N-nitrosomethylbenzylamine (NMBA): Analysis of cell proliferation, and mutations in H-ras and p53 genes. Carcinogenesis 1997;18:1477-84.  Back to cited text no. 14
    
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Prasad AS. Zinc in human health: An update. J Trace Elem Exp Med 1998;11:63-87.  Back to cited text no. 15
    
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Schwartz MK. Role of trace elements in cancer. Cancer Res 1975;35 (11 Pt 2):3481-7.  Back to cited text no. 16
    
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Sturniolo GC, Di Leo V, Barollo M, Fries W, Mazzon E, Ferronato A, et al. The many functions of zinc in inflammatory conditions of the gastrointestinal tract. J Trace Elem Exp Med 2000;13:3-39.  Back to cited text no. 17
    
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Newberne PM, Schrager TF, Broitman S. Esophageal carcinogenesis in the rat: Zinc deficiency and alcohol effects on tumor induction. Pathobiology 1997;65:39-45.  Back to cited text no. 18
    
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Çokuğraş, AN. Butyrylcholinesterase: structure and physiological importance. Turk J Biochem 2003;28:54-61.  Back to cited text no. 19
    
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Sarkarati B, Cokugras AN, Tezcan EF. Inhibition kinetics of human serum butyrylcholinesterase by Cd2+, Zn2+and Al3+: Comparison of the effects of metal ions on cholinesterases. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1999;122:181-90.  Back to cited text no. 20
    
21.
Bergmeyer HU. Cholinesterase. Methods of Enzymatic Analysis. Enzyme 2: Esterases, Glycosidases, Lyases, Ligases. 3rd ed., Vol. IV. Weinheim: Verlag Chemie; 1984. p. 63-74.  Back to cited text no. 21
    
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Smith JC, Holbrook JT, Danford DE. Analysis and evaluation of zinc and copper in human plasma and serum. J Am Coll Nutr 1985;4:627-38.  Back to cited text no. 22
    
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Pavithra V, Sathisha TG, Kasturi K, Mallika DS, Amos SJ, Ragunatha S. Serum levels of metal ions in female patients with breast cancer. J Clin Diagn Res 2015;9:BC25-7.  Back to cited text no. 23
    
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Makino T. Estimation of serum Zinc. Clin Chem Acta 1991;197:209-20.  Back to cited text no. 24
    
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Prabhu K, Naik D, Ray S. Significance of serum butyrylcholinesterase levels in oral cancer. Australas Med J 2011;11:374.  Back to cited text no. 25
    
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Syed M, Fenoglio-Preiser C, Skau KA, Weber GF. Acetylcholinesterase supports anchorage independence in colon cancer. Clin Exp Metastasis 2008;25:787-98.  Back to cited text no. 26
    
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Kuo HW, Chen SF, Wu CC, Chen DR, Lee JH. Serum and tissue trace elements in patients with breast cancer in Taiwan. Biol Trace Elem Res 2002;89:1-11.  Back to cited text no. 27
    
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    Tables

  [Table 1], [Table 2], [Table 3]



 

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