Exploration of Cadmium as an Endocrine Disruptor in Prostate Cancer Disparities

描述(申请人提供)：前列腺癌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，但可能是环境和生物因素造成的。体外研究表明，重金属镉是雄激素受体的内分泌干扰物。雄激素受体对正常的前列腺生长和发育是必不可少的，但也是治疗前列腺癌的主要药物靶点，因为它控制着参与疾病进展的过多下游靶点。先前的研究表明，与欧洲裔美国人相比，非裔美国人的尿镉和血镉水平更高，雄激素受体蛋白水平更高，前列腺组织中AR靶标的表达模式也不同。我们的初步数据(N=59)表明，非裔美国人的前列腺组织镉含量可能高于欧洲裔美国人。我们的数据还表明，镉与前列腺癌组织中雄激素受体蛋白的表达有关，但RACE改变了这种联系。因此，镉和雄激素受体相关性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标的表达/信号差异。在这项R21研究中，我们建议通过利用最初参与前列腺癌基因-环境相互作用(GECAP)(R01 ES11126)研究的明确的、种族多样化的前列腺切除病例队列(N=415，44%AA，诊断为1999-2004年)，进一步研究镉作为雄激素受体内分泌干扰物的作用。在前列腺癌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额外有毒和必需金属。我们还将测量肿瘤组织中的全基因组转录组。转录组包括由一组细胞中的基因转录表达的所有编码和非编码RNA。我们将确定在更大的队列中，前列腺癌组织镉水平是否与雄激素受体蛋白表达有关，并将确定RACE是否确实改变了镉和雄激素受体表达之间的关联。此外，我们将确定前列腺癌组织镉水平是否与前列腺癌侵袭性或生化复发有关。此外，我们还将研究镉水平和雄激素受体蛋白表达与非裔美国人和欧洲裔美国人前列腺癌转录组的联合关系。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标的表达差异，这些下游雄激素受体靶标在疾病进展中发挥作用，此外，这些差异可能在一定程度上解释了前列腺癌进展中的种族差异。如果我们的假设得到证实，GECAP数据集包含人口统计、临床和医学史、饮食、职业和遗传信息的大量资源，以调查可能解释这些发现的变量。

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.