Exploration of Cadmium as an Endocrine Disruptor in Prostate Cancer Disparities

镉作为内分泌干扰物在前列腺癌差异中的探索

• 批准号: 8875692
• 负责人: Christine Marie Neslund-Dudas
• 金额: $ 18.62万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875692
• 关键词: Address; Adverse effects; Affect; African; African American; Age; American; Androgen Receptor; Androgens; Binding; Biochemical; Biological; Biological Factors; Blood; Cadmium; Carcinogens; Cardiovascular Diseases; Cell Line; Cells; Clinical; Code; Complex; DNA Binding Domain; Data; Data Set; Diagnosis; Diet; Disease; Disease Progression; Drug Targeting; Employee Strikes; Endocrine; Endocrine Disruptors; Endocrine disruption; Environmental Risk Factor; Estrogen Receptors; European; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genome; Growth and Development function; Health; Heavy Metals; Human; In Vitro; Incidence; Inductively Coupled Plasma Mass Spectrometry; LNCaP; Lead; Malignant neoplasm of prostate; Measurement; Measures; Medical Genetics; Medical History; Metabolism; Metals; National Institute of Environmental Health Sciences; Neuroendocrinology; Obesity; Occupational; Occupations; Pathway interactions; Pattern; Play; Population; Prostate; Prostate Cancer therapy; Prostatectomy; Prostatic Neoplasms; Race; Recurrence; Reporting; Resources; Role; Signal Transduction; Smoking; Source; Steroid Receptors; Thyroid Diseases; Time; Tissues; Toxic effect; Tumor Tissue; Untranslated RNA; Work; base; cancer health disparity; cohort; deprivation; gene environment interaction; genetic information; hazard; male; malignant breast neoplasm; men; mortality; multidisciplinary; promoter; protein expression; racial difference; receptor; receptor expression; tumor; tumor progression; urinary

DESCRIPTION (provided by applicant): Tremendous race disparities exist in prostate cancer incidence and mortality. Reasons for these disparities remain unknown but are likely due to both environmental and biological factors. In vitro studies suggest that the heavy metal cadmium is an endocrine disruptor of the androgen receptor. The androgen receptor is essential for normal prostate growth and development but is also the primary drug target for treatment of prostate cancer as it controls a plethora of downstream targets involved in disease progression. Previous studies indicate that compared to European-Americans, African-Americans have had higher urinary and blood cadmium levels and, have higher androgen receptor protein levels and different patterns of AR-target expression in prostate tissue. Our preliminary data (N=59) suggests that African-Americans may have higher prostate tissue cadmium levels than European-Americans. Our data also suggests that cadmium is associated with androgen receptor protein expression in prostate tumor tissue but that race modifies the association. Therefore, race differences in the association between cadmium and the androgen receptor could lead to differences in expression/signaling of downstream androgen receptor targets involved in tumor aggressiveness and disease recurrence. In this R21 study, we propose to further investigate cadmium as an endocrine disruptor of the androgen receptor by capitalizing on a well-defined, ethnically diverse cohort of prostatectomy cases (N=415, 44% AA, diagnosed 1999-2004) that originally participated in the Gene-Environment Interaction in Prostate Cancer (GECAP) (R01 ES11126) study. In prostate tumor and adjacent non-tumor tissue, we will measure cadmium as well as a panel of additional toxic and essential metals that can affect cadmium toxicity. We will also measure the whole-genome transcriptome in tumor tissue. The transcriptome includes all coding and non-coding RNAs transcriptionally expressed by genes in a population of cells. We will determine whether prostate tumor tissue cadmium level is associated with androgen receptor protein expression in the larger cohort and will determine if race does indeed modify the association between cadmium and androgen receptor expression. Further, we'll determine whether prostate tumor tissue cadmium level is associated with prostate cancer aggressiveness or biochemical recurrence. In addition, we will examine the combined association of cadmium level and androgen receptor protein expression with regard to the prostate tumor transcriptome in African - and European- Americans. From our preliminary data and other existing reports, we hypothesize that race differences in the association of cadmium and the androgen receptor result in differences in expression of downstream androgen receptor targets that play a role in disease progression, and further, that these differences may in part explain race disparities in prostate cancer progression. If our hypothesis is confirmed, the GECAP data set contains an enormous resource of demographic, clinical and medical history, dietary, occupational and genetic information to investigate variables that may explain these findings.

描述（由申请人提供）：前列腺癌的发病率和死亡率存在巨大的种族差异。造成这些差异的原因尚不清楚，但可能是由于环境和生物因素。体外研究表明，重金属镉是雄激素受体的内分泌干扰物。雄激素受体对正常前列腺生长和发育至关重要，但也是治疗前列腺癌的主要药物靶标，因为它控制着参与疾病进展的大量下游靶标。先前的研究表明，与欧洲裔美国人相比，非洲裔美国人的尿和血镉水平较高，前列腺组织中雄激素受体蛋白水平较高，AR靶点表达模式不同。我们的初步数据（N=59）表明，非洲裔美国人可能有较高的前列腺组织镉水平比欧洲裔美国人。我们的数据还表明，镉与前列腺肿瘤组织中雄激素受体蛋白的表达有关，但种族改变了这种关联。因此，镉和雄激素受体之间的关联的种族差异可能导致参与肿瘤侵袭性和疾病复发的下游雄激素受体靶点的表达/信号传导的差异。在这项R21研究中，我们建议利用最初参与前列腺癌基因-环境相互作用（GECAP）研究（R 01 ES 11126）的明确定义的、种族多样的前列腺切除术病例队列（N=415，44% AA，1999-2004年诊断），进一步研究镉作为雄激素受体的内分泌干扰物。在前列腺肿瘤和邻近的非肿瘤组织中，我们将测量镉以及一组可能影响镉毒性的其他有毒和必需金属。我们还将测量肿瘤组织中的全基因组转录组。转录组包括由细胞群体中的基因转录表达的所有编码和非编码RNA。我们将确定前列腺肿瘤组织镉水平是否与雄激素受体蛋白表达相关，并确定种族是否确实改变了镉和雄激素受体表达之间的关联。此外，我们将确定前列腺肿瘤组织镉水平是否与前列腺癌的侵袭性或生化复发有关。此外，我们将研究镉水平和雄激素受体蛋白表达与非洲裔和欧洲裔美国人前列腺肿瘤转录组的联合关系。根据我们的初步数据和其他现有报告，我们假设镉和雄激素受体相关性的种族差异导致下游雄激素受体靶点表达的差异，这些靶点在疾病进展中发挥作用，并且进一步，这些差异可能部分解释前列腺癌进展中的种族差异。如果我们的假设得到证实，GECAP数据集包含了大量的人口统计学、临床和病史、饮食、职业和遗传信息资源，可用于调查可能解释这些发现的变量。