Synthetic Lethality between APOBEC-Induced DNA Damage and Base Excision Repair Inhibition as a Treatment Strategy for Breast Cancer
Abstract
Current breast cancer treatments involve drugs that block a tumor s growth by either stopping specific proteins involved in the cancer s uncontrolled cell division or by damaging a tumor cell s DNA. While these therapies are effective in many cases, drug resistance and severe side effects are still common. Identification and effective implementation of new breast cancer drugs is therefore essential. We have determined that many breast cancers inherently display high levels of DNA damage even without chemotherapy treatments. This damage is caused by the inappropriate activity of cellular proteins that convert normal cytosine bases in DNA to uracils, which cells see as DNA damage. Cells rely on DNA repair pathways to remove uracil from their DNA and thereby enable continued cell survival and division. We hypothesize that inhibiting these DNA repair pathways will increase the burden of DNA damage occurring in many breast cancers, ultimately resulting in tumor death. In this proposal, we therefore aim to develop and validate a test that we will ultimately use to identify breast cancer cells that have unusually high amounts of uracil in their DNA. With this knowledge in hand, we will investigate whether such cells are specifically sensitive to the loss of base excision repair, the major repair process responsible for removing uracil from cellular DNA. If successful, the proposed research will be a first step towards developing new effective breast cancer therapies that effect only tumor cells and therefore reduce the risk of severe side effects. This research will also develop assays that can be used to identify tumors that are likely sensitive to these treatments, and thereby insure drugs targeting tumor-specific DNA damage are effectively administered. Developing new breast cancer drugs that are highly specific to tumor cells as well as methods to ensure that patients receive the correct treatments is a critical step towards decreasing breast cancer illnesses in the coming years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510350
Entities
People
- Steven Roberts
Organizations
- United States Army
- Washington State University