Japanese Journal of Clinical Oncology 31:424-427 (2001)
© 2001 Foundation for Promotion of Cancer Research
Effects of Tamoxifen on the Serum Leptin Level in Patients with Breast Cancer
Departments of 1Medical Oncology and 2Epidemiology, Gulhane School of Medicine, Etlik, Ankara, Turkey
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Leptin is a peptide hormone that has a role in the regulation of body weight and has effects on metabolic, neuroendocrine, reproductive and hematopoietic systems. Breast cancer has also been associated with obesity and reproductive hormones, especially estradiol. Only a few studies have investigated the relation between plasma leptin and risk of breast cancer and only one study evaluated the effect of tamoxifen on leptin levels in patients with breast cancer.
Methods: We investigated serum leptin levels in gender-, body mass index (BMI)- and age-matched breast cancer patients and healthy individuals (58 of each).
Results: Serum leptin levels were measured by radioimmunoassay (Human Leptin RIA Kit). Serum leptin levels in the breast cancer patients were significantly higher than those in the control group (27.00 versus 17.65 ng/ml, p = 0.019). There were no differences with respect to BMI and age between control and breast cancer patients. There were no significant differences in BMI and leptin levels between pre- and postmenopausal patients (27.00 ± 1.39 and 27.19 ± 0.81 kg/m2, 26.81 ± 6.25 and 27.06 ± 2.98 ng/ml) (p > 0.05). We found no difference in serum leptin level between early and late stages of patients (22.38 versus 31.30 ng/ml, p = 0.086). However, the serum leptin level in patients using tamoxifen was significantly higher than that of patients not using tamoxifen (32.71 and 19.39 ng/ml, respectively p = 0.009). There was no correlation between CA 15-3 and leptin level (r = 0.069, p = 0.610).
Conclusion: High serum leptin levels seen in breast cancer patients are not related to stage of the disease or to cancer itself but may be associated with the use of tamoxifen.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Leptin is a protein that has 167 amino acids with a molecular mass of 16 kDa and is controlled by an obese gene that has a role in the regulation of body mass (1). Like other growth factors and cytokines, soluble leptin receptor, leptin binding proteins and free leptin are present in human serum (2). Leptin is produced according to lipid cell number and size. Plasma leptin levels are representative of body fat mass (3–6). It was found that plasma leptin levels increase in a logarithmic fashion with increase in body mass in mice (7). Leptin controls body mass and metabolism by affecting the metabolic, neuroendocrine, reproductive and hematopoietic systems (8).
There are regulatory dysfunctions in metabolic, neuroendocrine and other systems in cancer. However, there have been only a few reports about the role of leptin in these kinds of dysfunctions in cancer patients. It has been shown that leptin had no role in cancer cachexia in lung cancer patients (9). The leptin level in the circulation was found to be low in cachectic gastrointestinal cancer patients, but it was not affected by inflammatory response and cachexia due to cancer could not be attributed solely to leptin dysregulation (10).
Four studies have been published about the relationship between leptin and breast cancer. Tessitore and Vizio reported that the plasma leptin level and mRNA expression in adipose tissue in breast cancer patients were significantly higher than those in a healthy control group and it was postulated that plasma leptin levels in breast cancer patients could be used as a prognostic index (11). In another study on breast cancer cell cultures, leptin mRNA expression was found to be higher than in adipose tissue (12). However, there was no difference between a control group and patients in a study on premenopausal patients with in situ breast cancer (13). Marttunen et al. showed that antiestrogenic tamoxifen and toremifene increased serum leptin levels in postmenopausal breast cancer patients (14).
In this study, we evaluated serum leptin levels in 58 breast cancer patient and in order to try to clarify this issue.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
Fifty-eight female breast cancer patients (15 premenopausal and 43 postmenopausal) and 58 healthy female volunteers were enrolled in this study. Patients were staged according to the classification of the American Joint Cancer Committee (AJCC 97) as stage I–IIA and IIB (early stage, node negative, n = 28) and stage IIIA–B and IV (local advanced, node positive and metastatic, n = 30). All of the patients had invasive ductal carcinoma. Patients were also classified as to whether they received tamoxifen (n = 30) or not (n = 20) (Table 1). Written informed consent to participate in this study program was obtained from all patients prior to initiation of the study.
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Measurements of Serum Leptin and CA15-3 Levels
Serum leptin levels were measured by radioimmunoassay using a Human Leptin RIA Kit (Linco Research, St. Louis, MO). The sensitivity of the test was 0.5 ng/ml. The inter-assay coefficient of variation of the test was 8.3% at 4.9 ng/ml and 3.4% at 25.6 ng/ml. Blood samples were taken within 1 week after surgery. After 12 h of fasting, at 8 a.m., peripheral venous blood was taken. The blood samples were placed in tubes containing EDTA, centrifuged for 20 min at 2000 r.p.m. and the serum was separated. The samples were stored at –70°C until analysis. The blood samples from the tamoxifen-receiving group (20 mg/day) were taken from patients who had received tamoxifen at least for 6 months (6 months–3 years). None of the patients were taking any other drugs which could affect the serum leptin levels. When the blood samples were taken, 20 patients were using no medication, 30 were receiving only tamoxifen and eight were receiving chemotherapy.
The CA15-3 level was measured by chemiluminescence using a DPC Kit (Diagnostic Products, Los Angeles, CA).
Statistical Analysis
SPSS (Chicago, IL) version 7.5-Windows software was used for statistical analysis. Age, body mass index (BMI) and basal leptin levels of the cancer patients and the control group were compared by a non-parametric Wilcoxon Rank Sum W test. The comparison of patients and the control group for leptin levels was performed with a t-test. Leptin levels in patients receiving and not receiving tamoxifen were compared by the Mann–Whitney U-test. In the study of the correlation of leptin levels with CA15-3, the bivariate Pearson correlation test was used. Values p < 0.05 were accepted as statistically significant. Results were expressed as mean ± standard error.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There were no significant differences in age and BMI between the patient and control groups (52.03 and 51.83 years, 27.14 and 25.90 kg/m2) (p > 0.05). Also, there were no significant differences in BMI and leptin levels between pre- and postmenopausal patients (27.00 ± 1.39 and 27.19 ± 0.81 kg/m2, 26.81 ± 6.25 and 27.06 ± 2.98 ng/ml) (p > 0.05) (Table 1).
The mean serum leptin levels were 27.00 ± 2.71 ng/ml for the cancer patients and 17.65 ± 0.97 ng/ml for the control group. In breast cancer patients, the serum leptin level was significantly higher (p = 0.019) (Table 1). There was no correlation between serum leptin and CA 15-3 levels (r = 0.069, p = 0.610).
There were no significant differences regarding age, BMI and serum leptin level between early and late stage patients (50.93 and 53.07 years, 26.54 and 27.71 kg/m2, 22.38 and 31.30 ng/ml, p > 0.05) (Table 2).
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The serum leptin levels in patients receiving and not receiving tamoxifen were 32.71 ± 4.06 and 19.39 ± 3.51 ng/ml, respectively. The highest serum leptin levels were found in tamoxifen-receiving patients (p = 0.009) (Table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Studies on leptin levels in breast cancer patients and breast cancer cell cultures are limited in the literature. In Tessitore and Vizio’s study of breast cancer patients (11), the plasma leptin level and mRNA expression in adipose tissue were found to be significantly higher than those in a healthy control group and it was concluded that the plasma leptin level in breast cancer patients could be used as a prognostic index. In their study, leptin levels were evaluated in patients who had had mastectomy and were not taking chemotherapy. However, there was no information about patients who were receiving hormonal treatment. Estrogen and progesterone receptor levels were found to be higher than in the control group but this result was not discussed (11).
In the study of O’Brien et al. (12), leptin mRNA expression was found to be higher in three different breast cancer cell lines (MCF-7, T470 and MDAMB 231) than in adipose tissue. It was suggested that leptin could play a role in immunsuppression in breast cancer patients.
However, in a study carried out by Mantzoros et al. (13), 83 patients with premenopausal in situ breast cancer were compared with 69 control groups for their serum leptin levels, and no significant difference was found between these groups. It was concluded that leptin did not increase premenopausal in situ cancer risk.
In our study, the serum leptin level was higher in breast cancer patients than in the control group, and this increase was more prominent in tamoxifen-receiving patients. The increase was not related to the stage of the disease. Since the serum leptin level in patients who were not receiving tamoxifen was not different from that in the control group, it can be concluded that high serum leptin levels found in breast cancer patients may be due to tamoxifen use.
In Marttunen et al.’s study (14), 30 postmenopausal patients with breast cancer were randomized and treatment with either tamoxifen or toremifene was started. The serum leptin concentrations increased significantly in both groups after 6 months of treatment. It was concluded that antiestrogens may stimulate the synthesis and release of leptin in the adipocytes.
The mechanism of the increase in serum leptin levels in patients who receive tamoxifen is unclear. We can speculate that tamoxifen may contribute to increasing leptin mRNA expression through estrogen receptors. Further studies are needed to confirm this speculation.
In conclusion, high serum leptin levels seen in breast cancer patients are not related to the stage of the disease or to cancer itself, but may be associated with the use of tamoxifen.
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FOOTNOTES |
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+ For reprints and all correspondence: Ahmet Ozet, Department of Medical Oncology, Gulhane School of Medicine, 06018 Etlik, Ankara, Turkey. E-mail: aozet@gata.edu.tr
Abbreviations: ER, estrogen receptor; p, positive; n, negative; u, unknown; BMI, body mass index; T+, receiving tamoxifen; T–, not receiving tamoxifen; C, receiving chemotherapy; SEM, standard error of the mean
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Received February 26, 2001; accepted May 8, 2001.
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