Role of Pak Kinase in Breast Cancer Cell Cycle Progression
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Note: After one year of her fellowship in 2003, Dr. Maroto changed her montor, topic, project title, and aims.
 
 
 
 
 
 
 
 Original Award Title: DNA Damage Response Pathways in Breast Cancer Cells
 
 
 
 
 
 
 
 To ensure the high-fidelity transmission of genetic information, cells have evolved mechanisms to monitor genome integrity. Cells respond to DNA damage by activating a complex DNA-damage response pathway that must be coupled with DNA repair. An inability to respond properly and repair DNA damage leads to genetic instability, which is thought to enhance the rate of cancer progression. Normal human cells have two major checkpoints that are used to ensure that damaged DNA is not copied and is not passed on to new cells. Approximately 50% of breast cancers have a defect in one of these checkpoints. The survival of these checkpoint-defective cancerous cells is largely dependent on a second checkpoint.
 
 
 
 
 
 
 
 The major, well-characterized DNA damage response is at the G2/M transition of the cell cycle and involves the regulation of the complex Cdc2/Cyclin B activity, which controls the entry into mitosis. The overall goal of this project is to examine the mechanism by which the DNA damage checkpoint prevents cell cycle progression when DNA damage is sustained within mitosis. Thus, the research will better identify the role of upstream regulators of Cdc2/Cyclin B, which include checkpoint proteins like Chk1/Cds1 and ATM, and repair proteins like BRCA1. The different sensor and effector proteins involved in this second-level of DNA damage response will be studied to monitor how they get activated to protect the cell. The project will be done in non-breast cancer HeLa cells, which contain only the G2/M checkpoint operational, and in the breast cancer cell line HCC1937, which has no operational G2/M checkpoint and is also defective in BRCA1 gene, involved in breast cancer development. To monitor the response of ATM and downstream proteins to DNA damage by gamma irradiation occurring within mitosis ATM defective and non-defective cells will also be used. All these cells will be synchronized in mitosis by using the drug, nocodazole. Thus, the different sensor and effector proteins involved in this second-level of DNA damage response will be studied to monitor how they get activated to protect the cell. 
 
 
 
 
 
 
 
 Breast cancer therapy commonly requires the use of radiation or chemotherapy to rid the body of the remaining cancerous cells and thus, to reduce the risk of recurrence or metastasis. Radiation therapy and many forms of chemotherapy act by damaging DNA. Cancerous cells are more resistant to this kind of therapy, probably because of the failure of the checkpoints. The survival of these checkpoint defective cancerous cells is largely dependent on a remaining checkpoint. This is the basis of a major shortcoming of current therapy. Our work will provide molecular details by which the second checkpoint operates, so that it can be manipulated and enhance killing of cancerous cells.