Antiestrogen Regulation of Bladder Cancer

描述（由申请人提供）： 膀胱癌是美国第四大常见癌症，每年有超过63，210例新发病例和13，180例相关死亡。值得注意的是，男性膀胱癌的发病率是女性的三倍。已知雌激素受体介导雌激素的细胞内作用。两种受体亚型，雌激素受体-a（ER α）和ER β介导对雌激素和抗雌激素的核/基因组反应，并且它们表现出分离和重叠的组织分布和功能。ER α和ER？的表达在人类膀胱的尿道和逼尿肌中已经报道，并且在大鼠和小鼠中的研究表明ER是在膀胱上皮和平滑肌中表达的ER的主要形式。采用配体结合分析的实验表明ER存在于人类膀胱移行细胞癌中，并且免疫学方法证明ER α在12%-18%的测试膀胱癌中表达。然而，这与膀胱癌患者的预后无关。我们已经产生的数据表明：1）ER <$在大多数人膀胱移行细胞癌中表达，跨越广泛的阶段和等级，而ER α在<5%的肿瘤中表达; 2）ER <$在测试的多种膀胱癌细胞系中表达; 3）选择性雌激素受体调节剂（SERM），雷洛昔芬和他莫昔芬，体外抑制膀胱癌细胞系的生长和4）雷洛昔芬和4-羟基他莫昔芬减小在雌性裸鼠中生长的膀胱癌异种移植物的大小。基于这些发现，我们提出以下假设。SERM对膀胱癌细胞系的作用主要由ER介导，ER是人膀胱癌中表达的ER的主要亚型。ER的SERM治疗- 阳性膀胱细胞将抑制其生长，因此将是膀胱癌的有效化学预防策略。该假设将在以下两个具体目标中进行测试：1）研究雌激素受体的作用和雌激素受体配体调节膀胱癌细胞生长的能力，和2）研究选择性雌激素受体调节剂在人膀胱癌原位模型中的体内抗肿瘤作用。

DESCRIPTION (provided by applicant): Bladder cancer is the fourth most common cancer occurring in the United States, with each year bringing more than 63,210 new cases and 13,180 related deaths. Notably, the incidence of bladder cancer is three times higher in men than women. Estrogen receptors are known to mediate the intracellular actions of estrogens. Two receptor subtypes, estrogen receptor-a (ERa) and ER¿ mediate the nuclear/genomic responses to estrogens and antiestrogens, and they exhibit both separate and overlapping tissue distributions and functions. Expression of ERa and ER¿ have been reported in the urothelium and detrusor muscle of the human bladder, and studies in rats and mice indicate that ER¿ is the predominant form of ER expressed in the bladder epithelium and smooth muscle. Experiments employing ligand binding analyses indicate that ERs are present in transitional cell carcinoma of bladder in humans, and immunological approaches demonstrate ERa expression in 12%-18% of tested bladder cancers. This, however, did not correlate with the prognosis of bladder cancer patients. We have generated data indicating that: 1) ER¿ is expressed in the majority of human bladder transitional cell cancers across a broad spectrum of stage and grade, while ERa is expressed in < 5% of tumors; 2) ER¿ is expressed in multiple bladder cancer cell lines tested; 3) the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, inhibit growth of bladder cancer cell lines in vitro and 4) raloxifene and 4- hydroxytamoxifen reduce the size of bladder cancer xenografts grown in female nude mice. Based on these findings we propose the following hypothesis. SERM effects on bladder cancer cell lines are mediated mainly by ER¿ which is the predominate isoform of the ER expressed in human bladder cancer. SERM treatment of ER¿-positive bladder cells will inhibit their growth, and therefore will be an effective chemoprevention strategy for bladder cancer. This hypothesis will be tested in the following two specific aims: 1) To investigate the role of estrogen receptor and the ability of estrogen receptor ligands to regulate bladder cancer cell growth, and 2) To study the in vivo anti-tumor effect of selective estrogen receptor modulators in an orthotopic model of human bladder cancer.