Estrogen-ERbeta Axis In Disparity of Prostate Cancer

描述(申请人提供)：患有前列腺癌(PC)的非裔美国人(AA)的发病率和死亡率是欧洲裔美国人(EA)和任何其他种族的两倍，但导致这种健康差距的机制/S尚不清楚。PC细胞中不受控制的雄激素受体(AR)信号增加了肿瘤的发生，这是由雄激素剥夺疗法(ADT)控制的。然而，在AA-MAN中，ADT用于雄激素非依赖性和侵袭性肿瘤的复发。值得注意的是，患有PC的AA男性的循环雌激素水平显著高于EA男性。由于脂肪组织是男性雌激素的主要来源，而且PC的风险随着年龄和肥胖的增加而增加，因此肥胖和雌激素信号在PC进展过程中似乎有至关重要的联系。事实上，通过雌激素受体-β(ERP)的雌激素信号与侵袭性肿瘤的生长和转移有关。我们的抑制消减杂交(SSH)分析和基于RACE的cDNA微阵列相结合，显示在新鲜的显微解剖PC标本中，ERA共抑制物SAFB2和ERf3亚型都有选择性的上调。在AA来源的PC细胞系MDA-PCA-2b中，即使在没有雄激素的情况下，雌激素-ERP信号轴的激活也能激活PC细胞的AR反式激活和增殖反应。再者，再生障碍性贫血患者的脂肪干细胞(ADMSCs)可分泌雌激素，对肿瘤衍生因子作出反应，并在体外和体内促进PC细胞的生长。因此，我们假设，尽管进行了雄激素消融治疗，但雌激素-ERP轴激活的OFAR信号在AA患者的PC进展中起着关键作用。我们的假设将通过以下特定目的来检验：(1)评估SAFB2和ERb表达水平作为非裔美国人侵袭性PC的生物标志物和/或预后指标的临床应用价值。(2)研究雌激素-事件相关蛋白(ERP)轴在体外是否促进了AR介导的SAFB2表达的PC细胞的生长和转移。(3)体外研究AA-MEN来源的ADMSCs产生的局部雌激素是否参与了ADC诱导下的PC细胞的生长和转移，以及(4)在ADC作用下，全身和/或ADMSC来源的雌激素激活的ERP对PC肿瘤的生长有促进作用。相关性(参见说明)：发现可能导致再生障碍性贫血患者雄激素抵抗和侵袭性PC生长的替代信号通路将是至关重要的。雌激素-事件相关蛋白信号轴在PC进展中的关键作用以及脂肪干细胞来源的雌激素在PC细胞生长和转移中的作用，将为理解非裔美国人PC的不成比例发病率和死亡率提供新的线索，并将阐明易于实施的新的治疗策略。

DESCRIPTION (provided by applicant): African Americans (AA) with prostate cancer (PC) have twice the incidence and mortality than European Americans (EA) and any other ethnic groups, however, the mechanism/s linked to this health disparity is not understood. The uncontrolled androgen receptor (AR) signaling in PC cells increases tumor development which is controlled by androgen deprivation therapy (ADT) in patients. However, ADT selects for androgen- independence and recurrence of aggressive tumors in AA-men. Notably, AA-men with PC have significantly higher circulating estrogens than EA-men. Since adipose tissue is the major source of estrogens in men and since PC risk increases with age and obesity, there appears to be a crucial link between adiposity and estrogenic signaling in PC progression. Indeed, estrogenic signaling via the estrogen receptor-beta (ERP) is implicated in aggressive tumor growth and metastasis. Our combined suppressive subtractive hybridization (SSH) analysis and race-based cDNA microarrays, showed a selective up-regulation of both the ERa co- repressor, SAFB2 and the ERf3 isoform, in freshly microdissected PC specimen. In the AA-derived PC cell line MDA-PCa-2b, activation of estrogen-ERP signaling axis conferred AR transactivation and proliferative responses in PC cells, even in the absence of androgen. Furthermore, adipose stem ceils (ADMSCs) from AA-men secreted estrogens in response to tumor-derived factors and increased PC cell growth both in vitro and in vivo. We therefore hypothesize that activation ofAR signaling by estrogen-ERP axis is pivotal to the progression of PC in AA-men despite androgen ablation therapy. Our hypothesis will be tested by the following specific aims: (1) to evaluate the clinical utility of SAFB2 and ERb expression levels as biomarkers and/or prognostic indicators of aggressive PC in African Americans. (2) To determine if the estrogen-ERp axis augments AR-mediated growth and metastasis in SAFB2-expressing PC cells in vitro. (3) To investigate in vitro whether local estrogen production by ADMSCs from AA-men contributes to ERp-dependent enhanced growth and metastasis of PC cells under ADC in vitro, and (4) To demonstrate that ERp activation by systemic and/or ADMSC-derived estrogens increases growth of PC tumors under ADC in vivo. RELEVANCE (See Instructions): The discovery of alternate signaling pathways that may lead to androgen resistance and aggressive PC growth in AA-men, would be of crucial importance. A crucial role of estrogen-ERP signaling axis in PC progression and the contribution of adipose stem cell derived estrogens on growth and metastasis of PC cells, will provide new clues for understanding the disproportionate incidence and mortality due to PC in African American natients and will rifilineate novel theraneutic strategies that can be easily implemented..