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Antiestrogen Regulation of Bladder Cancer

膀胱癌的抗雌激素调节

基本信息

批准号：
7471237
负责人：
CAROLYN Louise SMITH
金额：
$ 7.68万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7471237
关键词：
4-Hydroxy-Tamoxifen Adult Bladder Bladder Urothelial Cell Bone and Cartilage Funding Breast Cancer Cell Growth Cancer Patient Cancer cell line Cell Proliferation Cells Cessation of life Chemoprevention Chemotherapy-Oncologic Procedure Cisplatin/Doxorubicin/Methotrexate/Vinblastine Cisplatin/Gemcitabine Common Neoplasm Data Diagnosis Drug or chemical Tissue Distribution Epithelium Estrogen Antagonists Estrogen Receptor 1 Estrogen Receptor 2 Estrogen Receptor Modulators Estrogen Receptors Estrogen receptor positive Estrogens Excision Exhibits Female Gastrointestinal tract structure Genomics Goals Growth Human Hyperplasia Immunotherapy In Vitro Incidence Invasive Kidney Knockout Mice Ligand Binding Ligands Liver Lung Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Modeling Mus Nuclear Nude Mice Numbers Operative Surgical Procedures Ovary Papillary Phenotype Pituitary Gland Play Prostate Protein Isoforms Radical Cystectomy Raloxifene Rate Rattus Recurrence Regulation Reporting Research Role Selective Estrogen Receptor Modulators Signal Transduction Skin Smooth Muscle Staging Survival Rate Systemic Therapy Tamoxifen Testing Testis Thyroid Gland Time Transitional Cell Carcinoma Treatment Protocols United States Urologic Cancer Urothelium Uterus Vagina Woman Xenograft procedure aged base bladder Carcinoma bladder transitional cell carcinoma cancer cell detrusor muscle in vivo intravesical male men outcome forecast prevent receptor research study response size tumor

项目摘要

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.

描述（由申请人提供）：膀胱癌是美国第四大常见癌症，每年新增病例超过 63,210 例，相关死亡人数为 13,180 例。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 (ERa) 和 ER¿ 介导对雌激素和抗雌激素的核/基因组反应，并且它们表现出独立和重叠的组织分布和功能。据报道，ERa 和 ER¿ 在人类膀胱的尿路上皮和逼尿肌中表达，并且对大鼠和小鼠的研究表明 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，免疫学方法表明 12%-18% 的测试膀胱癌中有 ERa 表达。然而，这与膀胱癌患者的预后无关。我们生成的数据表明：1) ER¿ 在大多数人类膀胱移行细胞癌中表达，跨越广泛的阶段和级别，而 ERa 在 < 5% 的肿瘤中表达； 2) ER¿在所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在体外抑制膀胱癌细胞系的生长，4) 雷洛昔芬和 4-羟基他莫昔芬可减小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。 SERM 治疗 ER¿ 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。这一假设将在以下两个具体目标中得到检验：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，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。