Urinary cadmium and risk of breast cancer

描述(申请人提供)：模拟雌激素影响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，镉都被证明具有强大的雌激素样活性，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列为已知的人类致癌物质。这种雌激素和致癌活性的结合使镉成为乳腺癌的一种特别令人担忧的污染物。一项中等规模的流行病学研究表明，一般人群中高四分之一人群普遍存在接触镉的风险，这意味着镉可能在乳腺癌中发挥重要作用；然而，这项研究使用的是确诊后收集的尿镉。因此，人们质疑镉含量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效果。鉴于支持镉与乳腺癌关系的机械性和初步流行病学证据，该项目旨在从丹麦饮食癌症与健康(DCH)前瞻性队列中严格调查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，如果不仅仅是这样，也是世界上少数几个有足够能力调查乳腺癌的队列之一，以及在诊断前收集的尿样，并可用于所有参与者。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，并根据有效的病例队列设计随机选择900名女性作为对照组(子队列)。女性人口将限制在基准线上的绝经后人口，因为大多数乳腺癌病例发生在绝经后女性。尿样将进行镉、其他金属和肌酐的分析。这项研究将对普通人群中镉暴露与乳腺癌之间的假设关系提供可靠和有价值的见解，并将评估锌摄入量和吸烟史是否会改变这些关系。分析还将根据导管和小叶组织学、原位/侵袭状态、雌激素受体阳性、癌症分期以及其他变量进行分层，以调查结果的敏感性和效果调整。这项拟议的研究将解决最近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，这些局限性涉及暴露评估的精确度、研究规模以及先前回顾设计中可能存在的偏见。如果这项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接触镉的预防潜力很大，因为人们已经很好地认识到了普通人群接触镉的主要来源。

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.