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The Functional Polymorphism of Erythropoietin Gene Rs1617640 G>T Is Not Associated with Susceptibility and Clinical Outcome of Early-Stage Breast Cancer

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The Functional Polymorphism of Erythropoietin Gene Rs1617640 G>T Is Not Associated with Susceptibility and Clinical Outcome of Early-Stage Breast Cancer ANTICANCER RESEARCH 32: 3473-3478 (2012) The Functional Polymorphism of Erythropoietin Gene rs1617640 G>T Is Not Associated with Susceptibility and Clinical Outcome of Early-stage Breast Cancer JOANNA SZKANDERA1,2, GUDRUN ABSENGER1,2, MICHAEL STOTZ1,2, MELANIE WEISSMUELLER1,2, THOMAS WINDER3, TANJA LANGSENLEHNER4, HELLMUT SAMONIGG1, WILFRIED RENNER2,5, WALTER SCHIPPINGER6 and ARMIN GERGER1,2 1Division of Clinical Oncology, Department of Internal Medicine, 2Research Unit Genetic Epidemiology and Pharmacogenetics, 4Department of Therapeutic Radiology and Oncology, 5Clinical Institute of Medical and Laboratory Diagnostics, Medical University of Graz, Graz, Austria; 3Department of Internal Medicine, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; 6Department of Internal Medicine, Albert Schweitzer Clinic, Graz, Austria Abstract. Recent data suggest that erythropoietin (EPO) transcription factors (2). The EPO gene is activated under plays a substantial role in cancer development and clinical hypoxic conditions through binding of the HIF1α and HIF1β outcome by stimulating cell proliferation, invasion and to the promoter, respectively (3). Its main function is to angiogenesis. A functional polymorphism (rs1617640 G>T) stimulate erythropoiesis by promoting proliferation and in the promoter region of the EPO gene increases EPO differentiation, or by inhibiting apoptosis of erythroid protein expression. In the present study, we investigated the progenitors (4). Its biological effects are mediated through association of EPO rs1617640 G>T with susceptibility and the binding to the erythropoietin receptor (EPOR), which clinical outcome of early-stage breast cancer. Genomic DNA belongs to the cytokine receptor type I superfamily (1, 5). of 539 female patients with histologically confirmed early- EPO was long considered to be a specific stimulator of stage breast cancer and 804 controls was genotyped for EPO erythropoiesis, but experimental findings have shown that its rs1617640 G>T. No association was found between EPO expression is not restricted to the hematopoietic system. rs1617640 G>T and early-stage breast cancer susceptibility Differential expression of EPO has been shown in other non- and clinical outcome (hazard ratio=1.24, 95% confidence hematopoietic tissues, such as brain astrocytes, breast interval=1.82-1.90, p=0.31). In conclusion, our findings epithelial cells and human reproductive organs, suggesting a suggest a lack of influence of EPO rs1617640 G>T on early- pleiotropic mechanism of action, extending well beyond the stage breast carcinogenesis and clinical outcome. maintenance of red cell mass (6-8). Furthermore, multiple investigators have documented EPO production in various Erythropoietin (EPO) is a glycoprotein hormone mainly tumor cell lines and cancer entities, including breast cancer produced in the adult kidney and fetal liver (1). EPO gene (9-13). Major signal-transduction pathways activated by EPO expression is regulated by inhibitory [GATA binding protein involve the Janus kinase (JAK)/signal transducer and 2 (GATA2), nuclear factor kappa-light-chain-enhancer of activator of transduction (STAT) and rat sarcoma activated B cells (NF-κB)] and stimulatory [hypoxia- (RAS)/mitogen-activated protein kinase pathways, which are inducible factors (HIFs), hepatocyte nuclear factor] essential for the inhibition of apoptosis and the stimulation of cell proliferation in response to this hormone (5, 14). Moreover, it has been demonstrated that exposure of tumor cells to EPO-stimulated tyrosine phosphorylation, DNA Correspondence to: Armin Gerger, MD, Priv.-Doz., Associate Prof., synthesis and proliferation, suggesting that EPO signaling is Research Unit: Genetic Epidemiology and Pharmacogenetics, biologically active in malignant cells (9, 10). Additionally, Division of Clinical Oncology, Department of Internal Medicine, recent data indicate that EPO is involved in angiogenesis and Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Tel: +43 31638580625, Fax: +43 31638513355, e-mail: invasion of neoplastic cells and may be important in breast [email protected] tumorigenesis (12, 15, 16). Mohyeldin et al. reported an EPO-mediated invasion through the JAK/STAT pathway in Key Words: Breast cancer, germline polymorphism, erythropoietin. head and neck squamous carcinoma cells (17). Furthermore, 0250-7005/2012 $2.00+.40 3473 ANTICANCER RESEARCH 32: 3473-3478 (2012) it has been demonstrated that EPO stimulates proliferation Vienna, Austria). Polymerase chain reaction (PCR) and evaluation in renal cancer cells (18). In endometrial carcinoma, EPO of fluorescence data were carried out as described elsewhere (23). signaling was shown to contribute to tumor progression and For each sample, one negative control containing water instead of DNA was added to check for contamination. For purposes of quality increased aggressiveness, identifying increased EPO control of genotyping, a total of 10% of the analyzed samples were expression as an independent prognostic factor (19). In re-analyzed. The investigator responsible for genotyping was prostate cancer, EPO was shown to regulate an blinded to the clinical dataset. autocrine/paracrine signaling pathway that influences growth and survival of cancer cells (20). In a recent study, Acs et al. Statistics. The primary endpoint of the study was disease-free demonstrated that EPO signaling inhibits hypoxia-induced survival (DFS). DFS was calculated from the date of diagnosis of apoptosis in human breast carcinoma cells and was early-stage breast cancer to the date of the first observation of tumor recurrence. DFS was censored at the last follow-up if the patient associated with poor prognosis (21). The TT genotype of a remained tumor-free at that time. Allelic distribution of the common gene variant in EPO, rs1617640 G>T, located in the polymorphism was tested for deviation from Hardy-Weinberg promoter region, leads to increased EPO protein expression equilibrium using χ2-test. The true mode of inheritance of the through an ecotopic viral integration site 1 (EVI1)/ melatonin polymorphism tested has not been established yet and we assumed 1 (MEL1) or activator protein 1 (AP1) enhancer binding site a co-dominant, additive, dominant, or recessive genetic model was and may be associated with cancer susceptibility and clinical appropriate. The association of the polymorphism with DFS was outcome (22). In the present study, we investigated the analyzed using Kaplan Meier curves and log-rank test. In the multivariate Cox regression analysis, the model was adjusted for association of EPO rs1617640 G>T with susceptibility and menopausal status, stage, histopathological grading, receptor status, clinical outcome in patients with early-stage breast cancer. human epidermal growth factor receptor 2 (HER2)/neu status and adjuvant treatment modalities. Case-wise deletion for missing Materials and Methods genotypes was used in univariate and multivariate analyses. Genotype frequencies in patients and controls were compared using χ2 tests. All analyses were performed using the SPSS statistical Study participants. A total of 539 female patients with histologically software package (SPSS Inc., Sunnyvale, CA, USA). confirmed breast cancer without distant metastases were included in this retrospective study. All patients were included in a breast Results cancer surveillance program between 2001 and 2009 at the Division of Clinical Oncology, Department of Internal Medicine, Medical Baseline patient characteristics, tumor biological factors, University of Graz, Austria, providing follow-up care at regular treatment modalities and their association with clinical outcome intervals (3-month intervals in years 1-3, 6-month intervals in years 4-5, and 12-month intervals in years 6-10 after curative surgery). are shown in Table I. The median age at time of diagnosis was Follow-up investigations included clinical check-up, laboratory, 57 years (range 29 to 84 years). The median follow-up duration radiological (bone scan, liver scan, chest X-ray, and mammograms), was 61.1 months (range 12 to 107 months). Follow-up data was and gynecological examination. A total of 804 healthy female missing for 38 (7.1%) patients. Genotyping was successful in controls were recruited from local health screening studies, the 520 (96.5%) patients and 799 (99.4%) controls. In failed cases, Salzburger Atherosklerose Präventionsprogramm bei Personen mit genotyping was not successful due to limited quantity and/or hohem Infarkt Risiko and the Grazer Diabetes Screening Programm. quality of extracted genomic DNA. The genotyping quality Controls with previous malignant disease were excluded from the present study. Blood samples were taken from all patients and control by subsample re-analysis provided a genotype controls, and stored at −20˚C. The present study was performed concordance of >99%. The allelic frequencies for the according to the Austrian Gene Technology Act, and has been polymorphism were within the probability limits of Hardy- approved by the Institutional Reviewer Board of the Medical Weinberg equilibrium. A statistically significant correlation was University of Graz. All participants gave written informed consent found between clinical outcome and tumor size, lymph node and were Caucasian. involvement and tumor stage (Table I). There was no significant association between EPO rs1617640 G>T and Candidate polymorphisms. The following pre-defined criteria for the breast cancer susceptibility (Table II).
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