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BREAST CANCER METASTATIC POTENTIAL--ANTIESTROGEN EFFECTS

乳腺癌转移潜力——抗雌激素作用

基本信息

批准号：
2103132
负责人：
JOSEPH Thomas PENTO
金额：
$ 12.77万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-02-18 至 1999-01-31
项目状态：
已结题

项目摘要

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.

肿瘤恶性的主要特征和主要原因乳腺癌患者的发病率和死亡率是肿瘤细胞转移到体内的远处部位。因此，它制定控制和治疗策略非常重要预防转移过程，以便成功治疗这种疾病疾病。我们之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，具有潜力抑制乳腺癌的生长和转移。侵袭性是转移细胞的基本特征。因此，拟议研究的主要目标是确定影响环丙基抗雌激素对乳腺癌细胞的作用及其机制使用 ER 阳性 MCF-7 和 ER 阴性 MDA-MB-231 进行侵袭性人类乳腺癌细胞。侵袭性涉及肿瘤的附着细胞基底膜，产生蛋白水解酶基质消化和肿瘤细胞迁移。据此，在体外侵袭试验将用于研究环丙基的影响抗雌激素对正常乳腺、MCF-7 和 MDA-MB-231 侵袭性的影响细胞。环丙基抗雌激素对实际细胞的影响运动、运动特性和动力学也将是使用延时在正常乳腺癌和乳腺癌细胞中确定视频显微镜。环丙基抗雌激素的作用这些细胞的形态、超微结构和细胞骨架使用扫描和透射电子显微镜进行检查。依恋肿瘤细胞向层粘连蛋白的转化已被证明可以启动级联反应转移过程中涉及的事件。据此，抑制环丙基抗雌激素对层粘连蛋白介导的细胞的影响本研究将评估与基底膜的附着。在此外，环丙基抗雌激素对释放和释放的影响蛋白水解酶的活性，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方面的抗转移活性沿着转移级联的步骤，从而建立治疗这些化合物的潜力。环丙基抗雌激素显示完全缺乏雌激素活性，急性毒性水平非常低并有效抑制乳腺癌细胞增殖和转移传播应优于目前可用的抗雌激素药物治疗和/或预防乳腺癌的转移后遗症。最后，这项研究将为肿瘤细胞提供重要的新信息运动与肿瘤细胞形态的关系侵袭性。