Estrogen-ERbeta Axis In Disparity of Prostate Cancer

描述（由申请人提供）：非裔美国人（AA）前列腺癌（PC）的发病率和死亡率是欧洲裔美国人（EA）和任何其他种族群体的两倍，然而，与这种健康差异相关的机制尚不清楚。PC细胞中不受控制的雄激素受体（AR）信号转导增加了肿瘤的发展，而肿瘤的发展是由患者的雄激素剥夺治疗（ADT）控制的。然而，ADT选择AA男性中的雄激素非依赖性和侵袭性肿瘤复发。值得注意的是，AA男性PC有显着较高的循环雌激素比EA男性。由于脂肪组织是男性雌激素的主要来源，并且由于PC风险随着年龄和肥胖而增加，因此肥胖和PC进展中的雌激素信号传导之间似乎存在关键联系。事实上，通过雌激素受体-β（ERP）的雌激素信号传导与侵袭性肿瘤生长和转移有关。我们结合抑制性消减杂交（SSH）分析和基于种族的cDNA微阵列显示，在新鲜显微解剖的PC标本中，ERa共阻遏物SAFB 2和ERf3同种型选择性上调。在AA衍生的PC细胞系MDA-PCa-2b中，雌激素-ERP信号轴的激活赋予PC细胞中的AR反式激活和增殖反应，即使在雄激素不存在的情况下。此外，AA-男性的脂肪干细胞（ADMSC）在体外和体内均分泌雌激素以响应肿瘤衍生因子并增加PC细胞生长。因此，我们推测，尽管雄激素阻断治疗，雌激素-ERP轴激活AR信号是AA男性PC进展的关键。我们的假设将通过以下具体目的进行检验：（1）评估SAFB 2和ERb表达水平作为非裔美国人侵袭性PC的生物标志物和/或预后指标的临床效用。(2)确定雌激素-ER β轴是否在体外增强表达SAFB 2的PC细胞中AR介导的生长和转移。(3)体外研究AA-男性ADMSC的局部雌激素产生是否有助于体外ADC下PC细胞的ER β依赖性增强的生长和转移，以及（4）证明全身性和/或ADMSC衍生的雌激素激活的ER β增加体内ADC下PC肿瘤的生长。 相关性（见说明）：发现可能导致AA男性雄激素抵抗和侵袭性PC生长的替代信号通路将至关重要。雌激素-ERP信号传导轴在PC进展中的关键作用以及脂肪干细胞衍生的雌激素对PC细胞生长和转移的贡献，将为理解非裔美国人中PC的不成比例的发病率和死亡率提供新的线索，并将产生新的治疗策略，可以很容易地实施。

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..