Urinary cadmium and risk of breast cancer

尿镉与乳腺癌风险

• 批准号: 8105900
• 负责人: Jaymie R Meliker
• 金额: $ 31.6万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105900
• 关键词: Accounting; Address; Agreement; Apoptosis; Biological; Biological Availability; Biological Markers; Biometry; Breast; Breast Cancer Cell; Breast Cancer Risk Factor; Cadmium; Carcinogenesis Mechanism; Carcinogens; Cessation of life; Cohort Studies; Creatinine; DNA Repair; Data; Databases; Depressed mood; Developed Countries; Diagnosis; Diagnostic Neoplasm Staging; Diet; Dietary Zinc; Disease; Dose; Ductal; Educational Status; Endocrine; Enrollment; Environmental Carcinogens; Environmental Epidemiology; Environmental Exposure; Environmental Pollution; Environmental sludge; Epidemiologic Studies; Epidemiology; Epithelial Cells; Estrogen Antagonists; Estrogen Receptor 1; Estrogen Receptors; Estrogen receptor positive; Estrogens; Exercise; Exposure to; Female; Female Breast Carcinoma; Fertilizers; Food; Frequencies; Gene Activation; General Population; Half-Life; Health; Histology; Hormone replacement therapy; Hormones; Human; In Situ; In Vitro; Incidence; Individual; Intake; International; International Agency for Research on Cancer; Kidney; Laboratories; Light; Lobular; Lung; Malignant Neoplasms; Measures; Mediating; Metallothionein; Metals; Modification; Outcome; Participant; Play; Population; Postmenopause; Prevention; Prospective Studies; Questionnaires; Regulation; Reproductive History; Research Design; Risk; Risk Factors; Role; Sampling; Smoking; Smoking History; Smoking Status; Source; Specimen; Spottings; Time; Tobacco smoking; Trace metal; United States; United States Food and Drug Administration; Urine; Woman; Zinc; cancer diagnosis; cancer epidemiology; cancer risk; cigarette smoking; cohort; comparison group; design; diet and cancer; exposed human population; high risk; in vivo; inorganic phosphate; insight; malignant breast neoplasm; member; modifiable risk; nutritional epidemiology; prospective; research study; treatment effect; urinary

DESCRIPTION (provided by applicant): Environmental contaminants that mimic the effects of estrogen have been suggested to contribute to the high incidence of breast cancer in Western populations. In both in vitro and in vivo experiments, cadmium has been shown to possess potent estrogen-like activity, including proliferation of breast cancer cells, activation and increased expression of estrogen regulated genes, and activation of the estrogen receptor-1. Further, cadmium is classified as a known human carcinogen by the International Agency for Research on Cancer. This combination of estrogenic and carcinogenic activity makes cadmium a contaminant of particularly high concern for breast cancer. One modest-sized epidemiologic study suggests risk at cadmium exposure levels common to the upper quartile of the general population implying that cadmium may play a substantial role in breast cancer; however this study used urine cadmium collected after diagnosis. As a result, it has been questioned whether increased cadmium is a risk factor for breast cancer, or whether it reflects the effects of treatment or disease. In light of mechanistic and preliminary epidemiologic evidence supporting a cadmium-breast cancer relationship, this project aims to rigorously investigate the association between urinary cadmium levels collected prediagnostically and risk of breast cancer in a case-cohort study population from the Danish Diet Cancer and Health (DCH) prospective cohort. This is one of the few, if not only, cohorts in the world with adequate power for investigating breast cancer along with urine samples collected pre-diagnostically and available on all participants. Among the 57,053 members of the DCH cohort we will identify 900 cases of female breast cancer, and randomly select 900 women as a comparison group (sub-cohort) according to the efficient case-cohort design. Female population will be limited to those postmenopausal at baseline because most breast cancer cases occur in postmenopausal women. Urine samples will be analyzed for cadmium, other metals, and creatinine. This study will provide reliable and valuable insight into the hypothesized association between cadmium exposure in a general population and breast cancer and will assess whether zinc intake and smoking history modify these relationships. Analyses will also be stratified by ductal and lobular histology, in situ / invasive status, estrogen receptor positive, stage of cancer, along with other variables to investigate sensitivity of results and effect modification. The proposed study will address pressing questions posed by recent results and will overcome several methodological limitations of previous studies related to precision of the exposure assessment, study size, and possible bias in previous retrospective designs. If the study shows an association between urinary cadmium level and risk of breast cancer, there is great potential for prevention with more extensive regulation to avoid population exposure, since primary sources of general population exposure to cadmium are well recognized. PUBLIC HEALTH RELEVANCE: Breast cancer accounts for 200,000 new cases and 40,000 deaths in the United States each year; few modifiable risk factors have been identified. Mechanistic and early epidemiologic evidence suggest that cadmium, a known lung carcinogen, mimics endocrine hormones and may contribute to the high incidence rates of breast cancer in Western industrialized nations. This study seeks to shed light on whether urinary cadmium, a biomarker of decades-long exposure, is associated with breast cancer using a case-cohort epidemiologic study design and the Danish Diet and Cancer Cohort, one of the few cohorts in the world with adequate power for investigating cancer outcomes along with urine samples collected pre-diagnostically and available on all participants.

描述（由申请人提供）：模拟雌激素作用的环境污染物被认为是导致西方人群乳腺癌高发病率的原因。在体外和体内实验中，镉已被证明具有有效的雌激素样活性，包括乳腺癌细胞的增殖，雌激素调节基因的激活和表达增加，以及雌激素受体-1的激活。此外，镉被国际癌症研究机构归类为已知的人类致癌物。这种雌激素和致癌活性的结合使镉成为乳腺癌特别高度关注的污染物。一项中等规模的流行病学研究表明，镉暴露水平对一般人群的上四分位数常见的风险，这意味着镉可能在乳腺癌中发挥重要作用;然而，这项研究使用了诊断后收集的尿镉。因此，人们质疑镉的增加是否是乳腺癌的风险因素，或者它是否反映了治疗或疾病的影响。根据支持镉与乳腺癌关系的机制和初步流行病学证据，本项目旨在严格调查丹麦饮食癌症与健康（DCH）前瞻性队列研究人群中诊断前收集的尿镉水平与乳腺癌风险之间的关联。这是世界上为数不多的，如果不是唯一的，有足够的权力调查乳腺癌沿着尿液样本收集诊断前和所有参与者。在DCH队列的57，053名成员中，我们将确定900例女性乳腺癌病例，并根据有效病例队列设计随机选择900名女性作为对照组（子队列）。由于大多数乳腺癌病例发生在绝经后女性中，因此女性人群仅限于基线时绝经后的女性。将分析尿液样本中的镉、其他金属和肌酐。这项研究将提供可靠的和有价值的洞察到镉暴露在一般人群和乳腺癌之间的假设关联，并将评估是否锌摄入量和吸烟史修改这些关系。还将根据导管和小叶组织学、原位/浸润状态、雌激素受体阳性、癌症分期沿着其他变量对分析进行分层，以研究结果的敏感性和效应修改。拟议的研究将解决近期结果提出的紧迫问题，并将克服先前研究的几个方法学局限性，这些局限性与暴露评估的精确度、研究规模和先前回顾性设计中可能的偏倚有关。如果研究表明尿镉水平与乳腺癌风险之间存在关联，那么通过更广泛的监管来避免人群暴露的预防潜力很大，因为一般人群接触镉的主要来源已得到充分认可。 公共卫生关系：在美国，乳腺癌每年有20万新发病例和4万例死亡;几乎没有发现可改变的风险因素。 机制和早期流行病学证据表明，镉，一种已知的肺癌致癌物质，模仿内分泌激素，并可能导致乳腺癌在西方工业化国家的高发病率。 这项研究旨在阐明尿镉是否与乳腺癌相关，尿镉是数十年暴露的生物标志物，使用病例队列流行病学研究设计和丹麦饮食和癌症队列，这是世界上少数几个有足够能力调查癌症结局的队列之一，沿着诊断前收集的尿液样本，可用于所有参与者。