BREAST CANCER METASTATIC POTENTIAL--ANTIESTROGEN EFFECTS

乳腺癌转移潜力——抗雌激素作用

• 批准号: 2103130
• 负责人: JOSEPH Thomas PENTO
• 金额: $ 13.99万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-18 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2103130
• 关键词: MCF7 cell; SDS polyacrylamide gel electrophoresis; analog; antineoplastics; basement membrane; breast neoplasms; cell adhesion; cell cycle; cell migration; chemoprevention; chemotaxis; collagenase; enzyme activity; estrogen inhibitor; estrogen receptors; human tissue; laminin; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer invasiveness; neoplasm /cancer pharmacology; neoplastic cell; scanning transmission electron microscopy; urokinase; video microscopy

A major characteristic of tumor malignancy and the primary cause of morbidity and mortality in patients with breast cancer is the ability of tumors cells to metastasize to distant sites in the body. Therefore, it is important to develop therapeutic strategies for the control and prevention of the metastatic process in order to successfully treat this disease. Our previous work indicates that cyclopropyl antiestrogens are very potent inhibitors of breast tumor cell growth and have the potential to inhibit the growth and metastatic spread of breast cancer. Invasiveness is a fundamental characteristic of metastatic cells. Thus, the major objective of the proposed study is to determine the influence and mechanism of the cyclopropyl antiestrogens on breast cancer cell invasiveness using both ER-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cells. Invasiveness involves the attachment of tumor cells to the basement membrane, production of proteolytic enzymes for matrix digestion and tumor cell migration. Accordingly, in vitro invasion assay will be used to study the influence of the cyclopropyl antiestrogens on the invasiveness of normal breast, MCF-7 and MDA-MB-231 cells. The influence of the cyclopropyl antiestrogens on actual cell movement, characteristics and kinetics of locomotion will also be determined in normal breast, and breast cancer cell using time-lapse videomicroscopy. The effect of the cyclopropyl antiestrogens on the morphology, ultrastructure and cytoskeleton of these cells will be examined using scanning and transmission electron microscopy. Attachment of the tumor cell to laminin has been shown to initiate a cascade of events involved in the metastatic process. Accordingly, the inhibitory effect of cyclopropyl antiestrogens on the laminin-mediated cellular attachment to the basement membrane will be evaluated in this study. In addition, the effect of cyclopropyl antiestrogens on the release and activity of proteolytic enzymes such as collagenase IV and plasminogen activator, which are also key factors in the metastatic process, will be determined in these cell lines. The results of this study will reveal the antimetastatic activity of cyclopropyl antiestrogens at several major steps along the metastatic cascade, and thus, establish the therapeutic potential of these compounds. Cyclopropyl antiestrogens which display a complete lack of estrogen activity, a very low level of acute toxicity and potent inhibition of breast cancer cell proliferation and metastatic spread should be superior to currently available antiestrogens in the treatment and/or prevention of the metastatic sequelae of breast cancer. Finally, this study will provide important new information on tumor cell locomotion and the relationship between tumor cell morphology and invasiveness.

肿瘤恶性肿瘤的主要特征和 乳腺癌患者的发病率和死亡率是 肿瘤细胞转移到体内远处。 因此，它 对于制定控制和控制策略很重要 预防转移过程，以便成功对待这一点 疾病。 我们以前的工作表明环丙基抗雌激素是 非常有效的乳腺肿瘤细胞生长抑制剂，并具有潜力 抑制乳腺癌的生长和转移扩散。 侵袭性是转移细胞的基本特征。 因此， 拟议研究的主要目的是确定影响 环丙基抗雌激素在乳腺癌细胞上的机制 使用ER阳性MCF-7和ER阴性MDA-MB-231的侵入性 人类乳腺癌细胞。 侵袭性涉及肿瘤的附着 细胞到地下膜，生产蛋白水解酶 基质消化和肿瘤细胞迁移。 因此，体外 入侵测定法将用于研究环丙基的影响 正常乳房，MCF-7和MDA-MB-231的抗雌激素 细胞。 环丙基抗雌激素对实际细胞的影响 运动的运动，特征和动力学也将是 在正常乳房和乳腺癌细胞中确定延时 视频显微镜。 环丙基抗雌激素对 这些细胞的形态，超微结构和细胞骨架将是 使用扫描和透射电子显微镜检查。 依恋 肿瘤细胞到层粘连蛋白已显示出启动的级联 转移过程中涉及的事件。 因此，抑制性 环丙基抗雌激素对层粘连蛋白介导的细胞的影响 在本研究中将评估对地下膜的附着。 在 另外，环丙基抗雌激素对释放的影响和 蛋白水解酶的活性，例如胶原酶IV和纤溶酶原 激活剂也是转移过程中的关键因素，将是 在这些细胞系中确定。 这项研究的结果将揭示 环丙基抗雌激素在几个主要的抗转移活性 沿着转移级联级别的步骤，从而建立治疗性 这些化合物的潜力。 环丙基抗雌激素显示 完全缺乏雌激素活性，急性毒性水平很低 以及对乳腺癌细胞增殖和转移性的有效抑制 传播应该优于当前可用的抗雌激素 治疗和/或预防乳腺癌的转移性后遗症。 最后，这项研究将提供有关肿瘤细胞的重要新信息 运动和肿瘤细胞形态与 侵入性。