|Year : 2018 | Volume
| Issue : 10 | Page : 583-586
The clinical importance of serum galectin-3 levels in breast cancer patients with and without metastasis
Turkan Ozturk Topcu1, Halil Kavgaci1, Meral Gunaldi2, Hakan Kocoglu3, Murat Akyol4, Ahmet Mentese5, Serap Ozer Yaman5, Asim Orem5, Feyyaz Ozdemir1, Fazil Aydin1
1 Department of Medical Oncology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
2 Department of Medical Oncology, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
3 Department of Internal Medicine, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
4 Department of Medical Oncology, Manisa Public Hospital, Manisa, Turkey
5 Department of Biochemistry, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
|Date of Web Publication||24-Sep-2018|
Department of Internal Medicine, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Zuhuratbaba, Tevfik Saglam Street, No. 11, 34147 Bakirkoy, Istanbul
Source of Support: None, Conflict of Interest: None
Objective: Studies have investigated expression status of galectin-3 (Gal-3), but very little is known about the importance of circulating Gal-3 in patients with breast cancer (BC). The purpose of the study was to investigate the clinical significance and potential diagnostic value of plasma Gal-3 levels in patients with BC.
Materials and Methods: Fifty-two patients with BC and 35 age-matched healthy controls were enrolled. Levels of Gal-3 were investigated in BC patients and healthy controls. Gal-3 levels were determined using ELISA method.
Results: Serum Gal-3 levels were significantly higher in BC patients than in controls (P = 0.002). Gal-3 levels did not significantly differ according to patients' statuses of lymph node involvement, hormone receptor, lymphovascular invasion, e-cadherin, menopausal, stage, serum hemostatic markers (prothrombin time, partial thromboplastin time, and international normalized ratio), platelet counts, mean platelet volume, lactate dehydrogenase, carcinoembryonic antigen, and carbohydrate antigen 15-3 values (P > 0.05 for all). A cut-off value of Gal-3 to predict BC was determined at ≥3.17 ng/ml with a sensitivity of 75.0%, a specificity of 65.71%, a positive and negative predictive values of 76.5 and 63.9%, respectively (area under the curve: 0.705 [95% confidence interval, 0.598–0.798], P = 0.0002).
Conclusion: Serum Gal-3 levels were significantly higher in BC patients and did not significantly differ according to clinical and tumoral characteristics of patients. Furthermore, there was no difference in Gal-3 levels between BC patients with and without metastatic disease. Serum Gal-3 levels can be used as an adjunct to other diagnostic or screening tests for BC regardless of clinical and tumoral characteristics of patients.
Keywords: Breast cancer, cut-off value, galectin-3, metastasis
|How to cite this article:|
Topcu TO, Kavgaci H, Gunaldi M, Kocoglu H, Akyol M, Mentese A, Yaman SO, Orem A, Ozdemir F, Aydin F. The clinical importance of serum galectin-3 levels in breast cancer patients with and without metastasis. J Can Res Ther 2018;14, Suppl S3:583-6
|How to cite this URL:|
Topcu TO, Kavgaci H, Gunaldi M, Kocoglu H, Akyol M, Mentese A, Yaman SO, Orem A, Ozdemir F, Aydin F. The clinical importance of serum galectin-3 levels in breast cancer patients with and without metastasis. J Can Res Ther [serial online] 2018 [cited 2020 Feb 26];14:583-6. Available from: http://www.cancerjournal.net/text.asp?2018/14/10/583/176425
| > Introduction|| |
Cancer is one of the today's main health problems and a major cause of death throughout the world. Breast cancer (BC) is the most common form of cancer in women and is a cause of high mortality and morbidity worldwide. The World Health Organization reports that more than 1.2 million people are diagnosed with BC annually. BC is a heterogenic disease with different phenotypes and biological characteristics. Targeted therapies such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 receptor (HER2/neu) produce better clinical outcomes. However, the prognosis is poor in patients with no molecular targets. New molecular targets, therefore, need to be identified to improve prognosis in BC.
Galectin-3 (Gal-3) is a multifunctional protein. It is a member of the galectin family and consists of a C-terminal domain (CD) and an N-terminal domain (ND). Nuclear translocation and secretion of Gal-3 are performed by ND, CD-associated invasion, and metastasis. Gal-3 causes uncontrolled proliferation, antiapoptotic effects, angiogenesis, and progression in patients with BC. Several mutations of Gal-3 have been observed in various cancers, including Pro64His mutation in BC. Gal-3 may thus represent a novel target for treatment in BC.
Increased Gal-3 levels are associated with inflammation and fibrosis in acute and chronic conditions. Inflammation induces genetic changes and increases the risk of cancer. Various studies have shown that Gal-3 increases the progression and metastatic potential of cancer through several pathways. It also performs several molecular functions, including cell proliferation, invasion, migration, apoptosis, and metastasis., Several studies in patients with different types of cancer have reported higher circulating Gal-3 levels than in healthy control groups. This has been shown in patients with lung, colorectal, ovarian, head and neck cancers. Gal-3 can be used as a potential prognostic factor for monitoring progression and mortality in cancer.,
Several studies have investigated increased expression of Gal-3, but very little is known about the importance of circulating Gal-3 in patients with BC. This study examined the clinical significance of serum Gal-3 in BC by using ELISA technique. The advantages of this method are that it is safe, noninvasive, and repeatable. The aim of this study was to evaluate plasma levels of Gal-3 in patients with BC and to compare them with healthy controls.
| > Materials and Methods|| |
Fifty-two patients with BC, who admitted to the outpatient medical oncology clinic at our hospital, were enrolled. Thirty-five age-matched controls were also enrolled in this case–control study for the comparison of serum levels of Gal-3. Pregnant subjects, patients with renal, lung or hepatic function impairment, coronary insufficiency or active infections, smokers, patients with diabetes mellitus, subjects using anticoagulants or antiaggregant drugs and hospitalized patients were excluded. Patients were staged according to the Sixth Edition of the American Joint Committee on Cancer. Blood samples were collected at the time of BC diagnosis (before surgical interventions and chemotherapy regimens). Our hospital's Ethical Committee approved the study, and informed consent was received from all patients and controls. Blood samples were collected in tubes containing 3.8% sodium citrate or K3 EDTA as an anticoagulant and serum separator. Samples were centrifuged at 3000 rpm for 10 min to obtain plasma and serum supernatants. The plasma and serum samples were then stored at −80°C until biochemical analyses. A Roche Hitachi Cobas 8000 autoanalyzer (Roche, Germany) was used for routine biochemical parameters and a Beckman Coulter autoanalyzer for complete blood count analysis. Prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR), and D-dimer were assayed using an automatic coagulation analyzer (STA-compact, Diagnostica Stago, Asnieres, France) in a routine setting.
Measurement of human galectin-3
Levels of human serum Gal-3 were determined using an enzyme-linked immunosorbent assay kit (R & D systems, Catalog No. DGAL30, P. R. China) following the manufacturer's instructions. The absorbance of samples was measured at 450 nm using a VERSA max tunable microplate reader (Designed by Molecular Devices in California, USA). The results were expressed as ng/ml.
The Kolmogorov–Smirnov test was used to determine data distribution. At analysis of differences between patient and control samples, the independent samples t-test was used for data with normal distribution and the Mann–Whitney U-test for nonnormally distributed data. Differences between groups before and after chemotherapy were determined using Wilcoxon's two related samples test. Pearson's correlation coefficient analysis was used to examine relationships between parameters. Receiver operating characteristic (ROC) analysis was used for the determination of the possible use of the markers for clinical differentiation between the patient and the control groups. When the area under the curve (AUC) was found to be significant, the cut-off values were determined, and sensitivity and specificity for that particular cut-off point were calculated as well. Results were evaluated in confidence interval (CI). Statistical significance was accepted as P < 0.05 in all tests.
| > Results|| |
Fifty-two patients with BC and 35 age-matched healthy controls were enrolled. The mean age of patients was 52.88 ± 11.0 years and of controls was 53.03 ± 11.4 years. No significant difference was identified in regard to age between patients and healthy controls (P = 0.953). Demographic and clinical characteristics of patients and controls are shown in [Table 1]. Mean serum Gal-3 level in patients was 3.90 ± 1.10 ng/ml and in controls was 3.14 ± 1.06 ng/ml. Gal-3 levels were significantly higher in the patients than in the controls (P = 0.002) [Table 1].
|Table 1: Demographic and clinical characteristics of both groups; and comparison of serum galectin-3 levels between patients and controls|
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No correlation was observed between patients' hemostatic markers (PT, PTT, and INR), platelet counts, and mean platelet volume (MPV) values and Gal-3 levels (P > 0.05). Furthermore, there were no correlation between patients' lymphocyte, neutrophil, hemoglobin, albumin, lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA 15-3) values, and Gal-3 levels (P > 0.05) (data not shown).
Gal-3 levels did not significantly differ according to patients' statuses of lymph node involvement (P = 0.725), hormone receptor (for PR P = 0.723; for ER P = 0.552; for HER2 P = 0.708), lymphovascular invasion (P = 0.823), e-cadherin (P = 0.714), menopausal (P = 0.373), and their stages (P = 0.756). Results of comparisons between Gal-3 levels and various clinical parameters in patients with BC are shown in [Table 2].
|Table 2: Results (median and range) of comparisons between galectin-3 levels and various clinical parameters of patients with breast cancer|
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As it was found a significant difference in Gal-3 levels between BC patients and healthy controls we tried to find an optimal cut-off value for Gal-3 to detect BC. The area under an ROC curve for Gal-3 to predict BC was determined at ≥3.17 ng/ml. This cut-off value had a sensitivity of 75.0%, a specificity of 65.71%, a positive and negative predictive values of 76.5 and 63.9%, respectively (AUC: 0.705 [95% CI, 0.598–0.798], P = 0.0002) [Figure 1].
|Figure 1: Receiver operating characteristics curve for serum galectin-3 for the diagnosis of breast cancer. Area under the curve for HSP70 is 0.705 with P = 0.0002|
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| > Discussion|| |
BC is the most common form of cancer in women and associated with high mortality. Therefore, new screening, diagnostic and therapeutic techniques are needed to be developed in order to improve outcomes. Gal-3 is found in the cytoplasm, cell surface, and nucleus, and its biological activity depends upon cellular location. It is released into the circulation. Cytoplasmic Gal-3 has been shown to be associated with tumor progression., Higher cytoplasmic Gal-3 has been reported in cutaneous squamous cell carcinoma than in infiltrative basal cell carcinoma, and a positive correlation exists between cytoplasmic Gal-3 and tumor size.
Dysregulated (up/down regulation) expression of Gal-3 in several types of malignant cells, including BC,, has been shown to be associated with increased metastatic capacity of the tumor. In BC, controversial results exist in regard to the relation between expression status of Gal-3 and metastatic capacity. In some studies, decreased or increased expression was found to be associated with progression of disease while other studies did not show any correlation between expression levels and metastatic capacity., Furthermore, its serum levels were shown to be associated with metastatic potential in some types of tumors. For example, elevated plasma Gal-3 levels are associated with the occurrence and metastasis of nonsmall cell lung cancer. In addition, plasma Gal-3 levels have been used as a biological indicator in the management and follow-up of stage III and IV melanoma patients. Previous studies have shown that Gal-3 levels were higher in patients with metastatic gastrointestinal carcinoma, metastatic prostate cancer, metastatic melanoma, nonsmall cell lung cancer than patients with nonmetastatic disease.
In contrast to Iurisci et al.'s study, which did not show any significant difference in serum Gal-3 levels between BC patients and healthy controls, in our study, serum Gal-3 levels were significantly higher in BC patients than in controls. Thus, we also tried to determine a cut-off point for Gal-3 and its level of ≥3.17 ng/ml was associated with moderate sensitivity (75%) and specificity (65.71%). Hence, serum Gal-3 could be an adjunct test to other diagnostic or screening tests for BC. Also in Iurisci et al.'s study, despite they did not show a significant difference in serum Gal-3 levels between healthy individuals and BC patients, a significant difference was seen between BC patients with and without metastasis. In contrast to this study, there was no difference in serum Gal-3 levels between patients with and without metastatic disease in our study. These different results related to serum Gal-3 levels and metastatic status of BC could be explained with controversial results of studies regarding expression pattern in BC. Thus, further studies are needed to clarify this point. Also, in our study, Gal-3 levels did not significantly differ according to patients' statuses of lymph node involvement, hormone receptor, lymphovascular invasion, e-cadherin, menopausal, and their stages.
| > Conclusion|| |
Serum Gal-3 levels were found significantly higher in BC patients than in controls. Also, in our study, Gal-3 levels did not significantly differ according to patients' statuses of lymph node involvement, hormone receptor, lymphovascular invasion, e-cadherin, menopausal, and their stages. No correlation was observed between patients' hemostatic markers (PT, PTT, and INR), platelet counts, and MPV values and Gal-3 levels. In addition, there was no correlation between patients' lymphocyte, neutrophil, hemoglobin, albumin, LDH, CEA, CA 15-3 values, and Gal-3 levels. In our study, there was no difference in Gal-3 levels between patients with and without metastatic disease. A cut-off value of ≥3.17 ng/ml for Gal-3 was associated with moderate sensitivity (75%) and specificity (65.71%) for predicting BC. Gal-3 can be used as an adjunct to other diagnostic or screening tests for BC regardless of clinical and tumoral characteristics of patients.
The main limitations of this study were the low patient numbers, the short follow-up time and the fact that cellular expression of Gal-3 in pathology specimens was not investigated.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29.
Kasami M, Uematsu T, Honda M, Yabuzaki T, Sanuki J, Uchida Y, et al.
Comparison of estrogen receptor, progesterone receptor and Her-2 status in breast cancer pre- and post-neoadjuvant chemotherapy. Breast 2008;17:523-7.
Schneider BP, Winer EP, Foulkes WD, Garber J, Perou CM, Richardson A, et al.
Triple-negative breast cancer: Risk factors to potential targets. Clin Cancer Res 2008;14:8010-8.
Menon RP, Hughes RC. Determinants in the N-terminal domains of galectin-3 for secretion by a novel pathway circumventing the endoplasmic reticulum-Golgi complex. Eur J Biochem 1999;264:569-76.
Gong HC, Honjo Y, Nangia-Makker P, Hogan V, Mazurak N, Bresalier RS, et al.
The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells. Cancer Res 1999;59:6239-45.
Nangia-Makker P, Wang Y, Raz T, Tait L, Balan V, Hogan V, et al.
Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer. Int J Cancer 2010;127:2530-41.
Kim SJ, Shin JY, Cheong TC, Choi IJ, Lee YS, Park SH, et al.
Galectin-3 germline variant at position 191 enhances nuclear accumulation and activation of ß-catenin in gastric cancer. Clin Exp Metastasis 2011;28:743-50.
Yang RY, Rabinovich GA, Liu FT. Galectins: Structure, function and therapeutic potential. Expert Rev Mol Med 2008;10:e17.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-44.
Yu LG. Circulating galectin-3 in the bloodstream: An emerging promoter of cancer metastasis. World J Gastrointest Oncol 2010;2:177-80.
Takenaka Y, Fukumori T, Raz A. Galectin-3 and metastasis. Glycoconj J 2004;19:543-9.
Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S. Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res 2000;6:1389-93.
Eliaz I. The role of galectin-3 as a marker of cancer and ınflammation in a stage IV ovarian cancer patient with underlying pro-ınflammatory comorbidities. Case Rep Oncol 2013;6:343-9.
Balan V, Wang Y, Nangia-Makker P, Kho D, Bajaj M, Smith D, et al.
Galectin-3: A possible complementary marker to the PSA blood test. Oncotarget 2013;4:542-9.
Califice S, Castronovo V, Bracke M, van den Brûle F. Dual activities of galectin-3 in human prostate cancer: Tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3. Oncogene 2004;23:7527-36.
van den Brûle FA, Waltregny D, Liu FT, Castronovo V. Alteration of the cytoplasmic/nuclear expression pattern of galectin-3 correlates with prostate carcinoma progression. Int J Cancer 2000;89:361-7.
Mayoral MA, Mayoral C, Meneses A, Villalvazo L, Guzman A, Espinosa B, et al.
Identification of galectin-3 and mucin-type O-glycans in breast cancer and its metastasis to brain. Cancer Invest 2008;26:615-23.
Moisa A, Fritz P, Eck A, Wehner HD, Mürdter T, Simon W, et al.
Growth/adhesion-regulatory tissue lectin galectin-3: Stromal presence but not cytoplasmic/nuclear expression in tumor cells as a negative prognostic factor in breast cancer. Anticancer Res 2007;27:2131-9.
Castronovo V, Van Den Brûle FA, Jackers P, Clausse N, Liu FT, Gillet C, et al.
Decreased expression of galectin-3 is associated with progression of human breast cancer. J Pathol 1996;179:43-8.
Le Marer N, Hughes RC. Effects of the carbohydrate-binding protein galectin-3 on the invasiveness of human breast carcinoma cells. J Cell Physiol 1996;168:51-8.
Liang Y, Li H, Hou SC, Hu B, Miao JB, Li T, et al.
The expression of galectin-3 and osteopontin in occult metastasis of non-small cell lung cancer. Zhonghua Wai Ke Za Zhi 2009;47:1061-3.
Kapucuoglu N, Basak PY, Bircan S, Sert S, Akkaya VB. Immunohistochemical galectin-3 expression in non-melanoma skin cancers. Pathol Res Pract 2009;205:97-103.
Buljan M, Šitum M, Tomas D, Miloševic M, Krušlin B. Prognostic value of galectin-3 in primary cutaneous melanoma. J Eur Acad Dermatol Venereol 2011;25:1174-81.
[Table 1], [Table 2]