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Metallothionein 2A Genetic Polymorphisms and Risk of Ductal Breast Cancer

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Metallothionein 2A Genetic Polymorphisms and Risk of Ductal Breast Cancer Clin Exp Med (2014) 14:107–113 DOI 10.1007/s10238-012-0215-4 SHORT COMMUNICATION Metallothionein 2A genetic polymorphisms and risk of ductal breast cancer Anna Krzes´lak • Ewa Forma • Paweł Jo´z´wiak • Agnieszka Szymczyk • Beata Smolarz • Hanna Romanowicz-Makowska • Waldemar Ro´zan_ ´ski • Magdalena Brys´ Received: 19 March 2012 / Accepted: 24 September 2012 / Published online: 6 October 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com Abstract Metallothioneins (MTs) are a family of metal (95 % CI: 1.29–2.89, pdominant \0.02) after adjustment for binding proteins that play an important role in cellular age, family history, smoking status, BMI, menarche, parity, processes such as proliferation and apoptosis. Metallothi- menopausal status and use of contraceptive and meno- onein 2A is the most expressed MT isoform in the breast pausal hormones] had a significantly increased risk of cells. A number of studies have demonstrated increased breast cancer in Polish population, as well as women with MT2A expression in various human tumors, including haplotypes, including variant allele of rs28366003 SNP breast cancer. We carried out an association study to (OR = 1.58, CI: 0.41–6.33, p global = 0.03). Our data examine whether MT2A gene polymorphisms are associ- suggest that the rs28366003 SNP in MT2A is associated ated with risk of breast cancer. Information on lifestyle risk with risk of breast cancer in Polish population. factors was collected via a self-administered questionnaire. Genotyping was conducted using polymerase chain reac- Keywords Metallothionein 2A Á Breast cancer Á SNP tion–restriction fragment length polymorphism technique. Three single nucleotide polymorphisms (SNP) rs28366003, rs1610216 and rs10636 were genotyped in 534 breast Introduction cancer cases and 556 population controls. One SNP in MT2A (rs28366003) showed a positive association with Metallothioneins (MTs) are a family of proteins with low breast cancer. Compared with homozygous common allele molecular mass (6–7 kDa), high content of cysteine and carriers, heterozygous for the G variant [odds ratio complete absence of aromatic amino acids [1–3]. MTs bind (OR) = 1.92, 95 % confidence interval (CI):1.28–2.81, to biologically essential metals like Zn and Cu and can p trend \0.01; the OR assuming a dominant model 1.93 participate in regulation of these metals homeostasis. Moreover, MTs absorb the heavy metals such as Cd, Pb, Hg and As and assist with their transportation and extrac- tion [1–4]. Apart from their role in protection of tissue Anna Krzes´lak and Ewa Forma contributed equally to this work. against heavy metals, MTs can act as potent antioxidants against oxidative damages [1–4]. They are known to par- A. Krzes´lak Á E. Forma Á P. Jo´z´wiak Á A. Szymczyk Á M. Brys´ (&) Department of Cytobiochemistry, University of Ło´dz´, ticipate also in cell proliferation and apoptosis which are Pomorska 141/143, 90-236 Lodz, Poland very important processes in carcinogenesis [5–7]. In e-mail: [email protected] human, MTs are encoded by a family of genes located on chromosome 16q13 consisting of ten functional MT iso- B. Smolarz Á H. Romanowicz-Makowska Department of Clinical Pathomorphology, forms. The encoded proteins are subdivided into four Polish Mother’s Memorial Hospital Research Institute, groups: MT1, MT2, MT3 and MT4 proteins. Human MT Rzgowska 281/289, 93-338 Lodz, Poland isoforms have tissue-specific expression patterns [3]. MTs expression increases in response to various inducers such W. Ro´zan_ ´ski 2nd Department of Urology, Medical University of Ło´dz´, as metals, interleukins, interferon, tumor necrosis factor Pabianicka 62, 93-513 Lodz, Poland alpha and glucocorticoid hormones [8]. 123 108 Clin Exp Med (2014) 14:107–113 A number of studies have demonstrated increased patients who had previously diagnosed with other types of expression of MT1 and MT2 mRNA and protein in various primary cancers (excluding skin cancer) were excluded. human tumors such as kidney, lung, nasopharynx, ovary, A group of 556 healthy Polish individuals were col- prostate, salivary gland, testes, urinary bladder, cervical, lected from the Polish Mothers Memorial Hospital endometrial, skin and pancreatic cancers as well as mela- Research Institute from periodic health checkups and used noma [7, 9, 10]. In some cases, high expression of MT1 as reference. They were non-related women who have and MT2 correlates with tumor grade/stage, chemotherapy never been diagnosed with breast tumors or other tumors resistance and poor prognosis. However, MT1/2 can also and were randomly selected and matched to the cases on be down-regulated in certain tumors, for example, hepa- 10 years age groups (age range 34–83, mean age tocellular carcinoma and liver adenocarcinoma [7]. 51.27 ± 11.18). We enrolled only Caucasian women born MT2A is the most expressed isoform in the breast cells. and living in central Poland (Ło´dz´ region). We queried the The MT2A mRNA expression is positively correlated with cancer registry database every 2 months and identified all histological grade [7]. Histological grade 3 tumors were histopathologically confirmed incident primary breast observed to have a higher expression of MT2A mRNA than cancer cases reported within 4 months of diagnosis pre- grade 1 and 2 tumors. Immunohistochemical studies have ceding the recruitment. Informed consent was obtained shown that cytoplasmic and/or nuclear MT1/2 protein from patients and controls, and the Ethical Committee expression is associated with tumor grade, increased approved the study. recurrence rate and poor survival in the highly malignant invasive ductal breast carcinomas [5, 7, 9, 10]. Some Lifestyle risk factors studies have shown an inverse correlation between MTs expression and progesterone and estrogen receptors posi- Study participants were interviewed using questionnaire tivity [11]. Based on correlation of MT expression and that included socio-demographic, health related informa- clinicopathological parameters of breast cancer showed in tion, smoking status, menstrual and reproductive histories many reports, Bay et al. [12] suggested that metallothio- and exogenous hormone use. A positive family history of nein is a promising prognostic biomarker in breast cancer. breast cancer was defined as reporting of breast cancer in Taking into account the potential role of MT2A in breast one or more first-degree relatives. Body mass index (BMI) carcinogenesis, we have analyzed an association between was calculated from current weight in kilograms divided by breast cancer and three known single nucleotide polymor- height in meter square (measurements were extracted from phisms (SNPs) of MT2A gene. We selected SNPs that patient’s medical record). Smoking was grouped into could potentially affect gene expression. The SNPs ana- ‘‘never,’’ ‘‘former’’ and ‘‘current’’ based on self-reported lyzed by us in this study concerned A/G transitions in usage. Participants who reported smoking at least 100 promoter region at loci -5 and -209 (rs28366003 and cigarettes in their lifetime and who, at the time of survey, rs1610216, respectively) and C/G transition in 3’UTR smoked either every day or some days were defined as region at locus ?838 (rs10636). Therefore, we compre- current smoker. Eight participants reported smoking at hensively evaluated the association of this SNP with breast least 100 cigarettes in their lifetime but had not been cancer risk in a Polish population-based case–control smoking for 1–2 months. They were classified as current study. smoker. Participants who reported smoking at least 100 cigarettes in their lifetime and who had not been smoking for at least 3 months were defined as former smoker. Par- Materials and methods ticipants who reported never having smoked 100 cigarettes were defined as never smoker. Natural age at menopause Study population was defined as the age at the last menstrual period, which can only be defined retrospectively after at least 12 con- This case–control study involved 534 women with invasive secutive months of amenorrhea. This last menstrual period ductal breast cancer (age range 34–81, mean age should not be induced by surgery or other obvious causes, 54.76 ± 7.35) recruited between May 2003 and November such as irradiation or hormone therapy. None of the women 2010. The patients had a confirmed diagnosis of ductal involved in the study had undergone a hysterectomy and breast cancer based on histopathological evaluation and oophorectomy. Regular drug use was defined as self-report were under treatment at the Polish Mothers Memorial use of oral contraceptives or menopausal hormones for Hospital Research Institute, Lodz, Poland. None of the 6 months or longer. For any missing survey data, patients recruited patients received preoperative chemo- or radio- were subsequently queried which lead to complete therapy. Patients with recurrence of breast cancer and responses by all participants. 123 Clin Exp Med (2014) 14:107–113 109 Questionnaire and the matching techniques comprised an initiation denaturation step at 94 °C for 4 min, followed by 30 cycles of 96 °C for 1 min, 61 °C for An analysis of the computerized medical records identified 1 min, 72 °C for 1 min and final extension step at 72 °C 916 ductal breast cancer patients in the age group for 10 min. MT2A -209A/G was amplified 35 cycles at an 30–85 years. From the same hospital registry of women annealing temperature of 62 °C for 1 min, and extension at undergoing periodic health checkups, a control population 72 °C for 10 min. The conditions for MT2A ?838C/G was of 1,082 individuals in the same age group (30–85 years) 30 cycles at 61 °C annealing temperature for 1 min and was randomly selected. A postal questionnaire was sent to extension at 72 °C for 10 min. Subsequently, RFLP anal- both the cases and controls. The response rate in the survey ysis was performed on 20 microliters each of the respective for the ductal breast cancer patients was 58.3 % and for the PCR products by subjecting them to the following controls 56.3 % thus leaving a group of n = 534 cases and restriction enzymes: at a 5 U concentration: Bsg I (at 37 °C a population of n = 609 controls.
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