Prostate Cancer Health Disparity: Role of PDEF

在非裔美国人(AA)男性中，前列腺癌的特点是侵袭性更强，范围更广 与高加索男性相比，高加索男性的转移、早期发病和死亡率增加。我们建议 评估PDEF(前列腺源性ETS因子)和TWIST-1在前列腺癌健康差异中的作用。这些研究 在本申请中提出的是由我们新的观察结果驱动的，即PDEF水平有逐步下降 在侵袭性表型增加的前列腺癌细胞和前列腺癌组织切片中 病人。我们还在多个临床数据集中观察到PDEF mRNA的表达在高 Gleason分级Pca和肿瘤转移。此外，我们观察到了PDEF之间的相互关系 和Twist-1在PCa组织中的表达及PDEF和Twist-1的表达可预测PCa的预后 生死存亡。在初步研究中，我们观察到前列腺癌细胞中PDEF的表达从 AA男性和侵袭性表型细胞中，PDEF表达的实验性调节 细胞迁移和克隆形成活性部分是通过促进腔分化来实现的。这些激动人心的预赛 数据构成了我们提出的假设的基础：第一，在非裔美国人男性中，PDEF可以作为一种 用于区分侵袭性前列腺癌和惰性疾病的功能标记物。第二个是“PDEF” 在前列腺癌中发挥转移抑制作用，部分是通过调节Twist-1的表达，以及第三 这“PDEF的缺失可以帮助我们对可能对DNA甲基转移酶抑制剂有反应的PCa患者进行分层”。 我们提出了三个目标来检验这些假设。目的1：建立PDEF表达水平的差异 非裔美国人和高加索人前列腺癌标本的等级匹配及其相关性 这些与患者预后有关；目的2：确定PDEF在前列腺癌转移和种族差异中的作用 使用体内模型系统，和；*目标3：评估有PDEF缺失的前列腺癌是否有更多的反应 有利于ADT(恩扎鲁胺)和DNA甲基转移酶抑制剂(氮胞苷和 地西他滨)与单用ATD相比。拟议的研究是创新的，因为这些研究将增强 了解PDEF在抑制前列腺癌转移中的作用并帮助我们评估PDEF的有效性 PDEF/Twist-1在早期检测可能患有侵袭性前列腺癌并增强的患者中的应用 转移潜能。我们的研究将对开发一种新的区分方法产生影响 前列腺癌的侵袭性和转移性表型来自一种惰性疾病，这将特别 使再生障碍性贫血男性受益，减少前列腺癌治疗结果中的种族差异。

In African American (AA) men prostate cancer is characterized by higher aggressiveness, more extensive metastases, early onset, and increased mortality rates compared to those in Caucasian men. We propose to evaluate role of PDEF (Prostate Derived Ets Factor) and TWIST-1 in PCa health disparity. The studies proposed in this application are driven by our novel observations that there is graded decrease in PDEF levels in prostate cancer cells with increasing aggressive phenotype and in prostate cancer tissue sections of patients. We also observed in multiple clinical data sets that PDEF mRNA expression is decreased in high Gleason grade PCa and in tumor metastasis. Moreover we observed a reciprocal relationship between PDEF and Twist-1 expression in PCa tissues and that PDEF and Twist-1 expression could predict PCa patient survival. In preliminary studies we observed that PDEF expression is decreased in prostate cancer cells from AA men and in cells with aggressive phenotype, and experimental modulation of PDEF expression modulates cell migration and clonogenic activity in part by promoting luminal differentiation. These exciting preliminary data form the basis of our proposed hypothesis: First, that, “ In African American Men PDEF could serve as a functional marker for distinguishing aggressive prostate cancer from an indolent disease.” Second that “PDEF functions as a metastasis suppressor in prostate cancer in part by modulating expression of Twist-1”, and third that “Loss of PDEF can help us stratify PCa patients that might respond to DNA methyl transferase inhibitors”. We propose three aims to test these hypothesis. AIM 1: To establish differences in expression levels of PDEF between grade-matched Prostate Cancer specimens from African American and Caucasian men and correlate these with patient outcomes; AIM 2: To determine the role of PDEF in PCa metastasis and racial disparity using in vivo model systems, and ; *AIM 3: To evaluate if prostate cancers with PDEF loss respond more favorably to combination of ADT (Enzalutamide) and DNA methyl-transferase inhibitors (azacytidine and decitabine) as compared to ATD alone. The proposed studies are innovative as these will enhance understanding of role of PDEF in suppressing prostate cancer metastasis and help us evaluate usefulness of PDEF/Twist-1 in early detection of patients that may harbor aggressive prostate cancer with enhanced metastatic potential. The impact of our study will be on the development of a new method to distinguish aggressive and metastatic phenotype of prostate cancer from an indolent disease, which will particularly benefit AA men, and reduce ethnic disparity in in prostate cancer treatment outcomes.