ESTROGENIC ACTION IN ENDOMETRIAL VERSUS BREAST CANCER

子宫内膜癌与乳腺癌中的雌激素作用

• 批准号: 2203396
• 负责人: Kimberly K. Leslie
• 金额: $ 2.59万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2203396
• 关键词: breast neoplasms; clone cells; drug adverse effect; endometrium; estrogen receptors; estrogens; female reproductive system neoplasm; gene expression; hormone related neoplasm /cancer; human tissue; northern blottings; polyploidy; tamoxifen; transcription factor; transfection; western blottings

The National Surgical Adjuvant Breast and Bowel Project, sponsored by the National Cancer Institute, seeks to treat 16,000 healthy women with the estrogenic agonist/antagonist tamoxifen citrate as prophylaxis against breast cancer. One of the side effects of such therapy appears to be an increase in the incidence of endometrial cancer. Two important obstacles have hampered research concerning the link between estrogenic stimulation and tumorigenesis in the endometrium. First, although well- differentiated endometrial cancer is a classic hormone dependent disease, endometrial cell lines which serve as models for investigation rarely retain the differentiated phenotype of hormone responsiveness in vitro which is the hallmark of the biological disorder. Second, hormonal actions in breast cancer have been extensively studied, yet important differences in ligand-especially antiestrogen-action have been revealed which make it unreliable to assume that estrogenic compounds act similarly in these two hormone-responsive tissues. We hypothesize that estrogens and antiestrogens may have unique receptor-mediated effects in the endometrium, perhaps associated with altered estrogen receptor/nuclear protein interactions, which impact upon transcription in a tissue-specific manner. To test this hypothesis and to begin the study of estrogenic action in endometrial versus breast cancer, the following aims are proposed. (1) Endometrial and breast cancer model cell lines that are hormone- dependent will be created by stable transection of estrogen receptors (ER). The progression from hormone-sensitive to hormone to hormone- independent growth, as evidenced by tissue-specific gene expression in response to hormonal stimulation will be studied in detail, and will be used to monitor the development of the models. (2) Endometrial and breast cancer cells stably expressing estrogen receptors will be grown in the presence of estrogens and antiestrogens to assess tissue-specific hormonal effects. Tumor remodeling under hormonal stimulation will be compared between endometrial and breast cancer cells by determining changes in cell subpopulations, DNA ploidy and gene expression. (3) Far- Western blotting will be carried out with radiolabeled estrogen receptors bound to endometrial and breast protein nuclear extracts to determine whether cell-specific transcription factors interact with estrogen receptors. This initial screen will serve as a guide to future studies. Future experiments will seek to directly clone the factors which interact with ER using the novel two hybrid yeast system. Studies addressing estrogen and antiestrogen action in endometrial cancer are urgently needed before recommending tamoxifen as a therapeutic agent for general use.

国家手术辅助乳房和肠项目，由 国家癌症研究所（National Cancer Institute）试图用 雌激动剂/拮抗他莫昔芬柠檬酸盐作为预防剂 乳腺癌。 这种疗法的副作用之一似乎是 子宫内膜癌的发生率增加。 两个重要的障碍 是否阻碍了有关雌激素刺激之间联系的研究 子宫内膜中的肿瘤发生。 首先，虽然很好 分化的子宫内膜癌是一种经典的激素依赖性疾病， 子宫内膜细胞系很少用作研究模型 保留体外激素反应性的分化表型 这是生物障碍的标志。 第二，荷尔蒙 乳腺癌的作用已经进行了广泛的研究，但很重要 配体的差异，尤其是抗雌激素作用 这使得假定雌激素化合物ACT是不可靠的 同样，在这两种激素反应性组织中。 我们假设这一点 雌激素和抗雌激素在 子宫内膜，可能与雌激素改变有关 受体/核蛋白相互作用，影响转录 以组织特异性的方式。 检验这一假设并开始 研究子宫内膜与乳腺癌中的雌激素作用的研究， 提出了以下目标。 （1）激素 - 子宫内膜和乳腺癌模型细胞系 依赖者将通过雌激素受体的稳定横向产生 （ER）。 从激素敏感到激素到激素的发展 独立生长，如组织特异性基因表达所证明的 将详细研究对激素刺激的反应，并将 用于监视模型的开发。 （2）子宫内膜和 将稳定表达雌激素受体的乳腺癌细胞生长 在存在雌激素和抗雌激素的情况下，以评估组织特异性 激素效应。 在激素刺激下进行肿瘤重塑将是 通过确定子宫内膜和乳腺癌细胞之间的比较 细胞亚群，DNA倍性和基因表达的变化。 （3）远处 - 蛋白质印迹将使用放射标记的雌激素受体进行 绑定到子宫内膜和乳腺蛋白核提取物以确定 细胞特异性转录因子是否与雌激素相互作用 受体。 最初的屏幕将作为未来研究的指南。 未来的实验将寻求直接克隆相互作用的因素 使用ER使用新颖的两个混合酵母系统。 研究解决 雌激素和子宫内膜癌的抗雌激素作用紧急是 在推荐他莫昔芬作为一般治疗剂之前需要 使用。