Analysis of the DNA Damage Signaling Network Important for Prevention of Breast Cancer

Principal Investigator: ELLEDGE, STEPHEN J
Institution Receiving Award: BAYLOR COLLEGE OF MEDICINE
Program: BCRP
Proposal Number: BC000868
Award Number: DAMD17-01-1-0134
Funding Mechanism: Idea Award
Partnering Awards:
Award Amount: $451,500.00


Women with germline mutations in the breast and ovarian cancer gene 1 (Brca1) have an approximately 50% lifetime risk of developing ovarian cancer and an almost 90% chance of breast cancer. Brca1 mutations account for a significant percentage of all breast cancer cases. So far, there is only a small role for Brca1 mutations in sporadic cases of breast cancer. However, it is possible that improper regulation of Brca1 function might contribute to some of these cases. It appears that the main role for the Brca1 protein in cells is to prevent the accumulation of mutations in key growth regulatory genes in response to DNA damage. Mutations occur in genes when the DNA encoding those genes are damaged by chemicals or irradiation. Normal cells have an elaborate surveillance mechanism, called a checkpoint, that detects DNA damage and prevents the accumulation of mutation. In response to DNA damage, cells activate these checkpoint pathways to induce the expression of DNA repair genes to repair the damage. These pathways also instruct the cells to cease proliferation to prevent the replication of the damage and the generation or irreparable mutations. Brca1 is involved in repairing DNA damage and preventing mutations in key growth regulatory genes.

It appears that there is a whole network of tumor suppressor genes that work together to control the response to DNA damage to repair damage. We have found that Brca1 works together with the ATM checkpoint and tumor suppressor protein and Rad50/Mre11/Nbs1 protein complex found mutant in a second familial cancer syndrome, NBS. This grant proposes to study how changes in the Brca1 protein that occur in response to DNA damage allow it to activate DNA repair pathways to prevent mutations due to DNA damage and to prevent cancer. These studies have direct relevance to the understanding of breast cancer because the genes involved in these pathways are clearly involved in breast cancer. Hopefully, having a thorough understanding of these pathways will allow us to both prevent cancers in families harboring mutations in these genes and to cure cancers defective in these genes.