Validate Mitotic Checkpoint and Kinetochore Motor Proteins in Breast Cancer Cells as Targets for the Development of Novel Anti-Mitotic Drugs
Abstract
The kinetochore is a chromosomally associated structure that is essential for accurate chromosome segregation in mitosis. Kinetochores physically link chromosomes to the spindle but also monitor these interactions through the spindle checkpoint pathway. As kinetochores function specifically in mitosis, it is a highly desirable target for development of novel anti-cancer drugs. Toward this end, we are using RNAi technology to block the expression of a select group of kinetochore proteins to determine their importance to the survival of breast cancer cells. Initial studies showed that depletion of the hBUB 1 checkpoint protein from Hela cells prevented cells from arresting in mitosis in the presence of microtubule inhibitors. Loss of hBUB 1 prevented other checkpoint proteins from assembling onto kinetochores. Thus, hBUB I appears to specify the assembly of a subdomain of the kinetochore that is critical for checkpoint functions. We have expanded our studies to include the breast cancer cell lines MCF-7 and MDA-486. We will examine whether MCF7 and MDA468 cells respond in the same way as Hela cells responded to loss of hBUB 1 and other kinetochore proteins. These studies may reveal that the kinetochore is a valid target for the development of novel anti-mitotic agents. In addition, it is possible that inhibition of kinetochore functions may sensitize cells to conventional chemotherapeutics such as vinblastine and paclitaxal.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADA407481
Entities
People
- Timothy J. Yen
Organizations
- Fox Chase Cancer Center