ROLE OF A NEW ETS FACTOR, PDEF, IN PROSTATE CANCER

前列腺癌已经成为老年人中最常见的实体癌。 男人虽然雄激素消融治疗，手术和放射治疗， 有效的治疗局部前列腺癌，没有有效的 转移性雄激素非依赖性疾病患者的治疗。 雄激素非依赖性晚期前列腺癌的不良预后反映了 部分原因是缺乏对肿瘤基本生物学的了解。特别是， 人们对引发这种转化的分子机制知之甚少 从最初的雄激素依赖型癌症转变为雄激素非依赖型癌症。我们的目标是 了解一种新的前列腺上皮特异性转录的作用， 因子，PDEF（前列腺衍生Ets因子），Ets转录的成员 因子/癌基因家族在人前列腺癌中的作用。PDEF表示为 正常人前列腺腔上皮细胞及初步结果 表明PDEF表达在肿瘤的癌性部分中升高， 前列腺PDEF作为强转录因子独立于雄激素发挥作用， PSA和PSMA启动子的增强子，这两种诊断标志物用于 监测雄激素依赖性和非依赖性前列腺癌。激活MAP 激酶显著增强PDEF介导的转录激活。PDEF还 与雄激素受体相互作用并协同诱导 PSA基因因此，我们的假设是PDEF绕过或激活了 雄激素受体，从而有助于从最初的进展， 雄激素依赖性前列腺癌转变为雄激素非依赖性癌症。我们 建议确定Ets家族的这一新成员在以下方面的作用： 前列腺癌的形成和进展以及使用这种新的 作为另一种诊断工具和潜在的治疗靶点。因此，在本发明中， 具体目标是： 具体目标#1。PDEF在前列腺癌的发展中是否起着至关重要的作用 还是进步 具体目标#2 PDEF是前列腺特异性PSA基因的重要调节因子吗 表情？ 具体目标#3 PDEF活性能解释前列腺癌的转化吗 细胞对雄激素的依赖性由于Ets家族在 调节各种组织和分化特异性基因， Ets家族的几个成员在各种人类疾病中的直接影响 PDEF有望在前列腺上皮细胞中发挥作用， 转化或前列腺癌进展。

DESCRIPTION: Prostate cancer has become the most common solid cancer in older men. Although androgen ablation therapy, surgery and radiation therapy are effective for the treatment of local prostate cancer, there is no effective treatment available for patients with metastatic androgen-independent disease. The poor prognosis for androgen-independent advanced prostate cancer reflects in part the lack of knowledge about the tumor's basic biology. In particular, very little is known about the molecular mechanisms that trigger the conversion of an initially androgen-dependent cancer to androgen-independence. Our goal is to understand the role of a novel prostate epithelium-specific transcription factor, PDEF (Prostate Derived Ets Factor), a member of the Ets transcription factor/oncogene family in human prostate cancer. PDEF is expressed in the luminal epithelial cells of normal human prostate and preliminary results indicate that PDEF expression is elevated in cancerous portions of the prostate. PDEF acts independently of androgen as a strong transcriptional enhancer of the PSA and PSMA promoter, two diagnostic markers used for monitoring androgen-dependent and -independent prostate cancer. Activated MAP kinases drastically enhance PDEF mediated transcriptional activation. PDEF also interacts and cooperates with the androgen receptor in inducing expression of the PSA gene. Thus, our hypothesis is that PDEF bypasses or activates the androgen receptor and thereby contributes to the progression from an initially androgen-dependent prostate cancer to an androgen-independent cancer. We propose to determine the role of this novel member of the Ets family in prostate cancer formation and progression and the possibility to use this new factor as another diagnostic tool and as a potential therapeutic target. Thus, the specific aims are: Specific Aim #1. Does PDEF play a crucial role in prostate cancer development or progression? Specific Aim #2. Is PDEF a critical regulator of prostate-specific PSA gene expression? Specific Aim #3. Can PDEF activity explain the conversion of prostate cancer cells to androgen-independence? Due to the importance of the Ets family in regulation of various tissue- and differentiation-specific genes and due to the direct implication of several members of the Ets family in various human cancers, PDEF is expected to play a role in prostate epithelial cell transformation or prostate cancer progression.