Rendering DNA Repair Defective by Targeting Wild-Type BRCA1 Nuclear Shuttling in Sporadic Breast Cancer as a Therapeutic Strategy
Abstract
Agents targeting DNA double strand break repair (DSBR) deficiency, such as PARP1 inhibitors, are highly selective in killing BRCA1-mutated breast tumors, and the toxicity is minimal in mouse models. However, more than 90% of breast cancers are sporadic, which carry wild-type (wt) BRCA1 and are proficient in DSBR. BRCA1 is a nuclear shuttling protein, which regulates homologues recombination (HR)-mediated DSBR when nuclear and enhances apoptosis when cytoplasmic. BARD1 retains BRCA1 in the nucleus, whereas ionizing radiation (IR) induces p53-dependent export of BRCA1 to the cytosol. This research project is to test the hypothesis: whether targeting BRCA1 from the nucleus to the cytoplasm will render sporadic breast cancer cells become defective in DSBR and enhance apoptosis. Furthermore, if the combination of induced repair deficiency and augmented apoptosis will render sporadic breast cancers become highly susceptible to selective killing by PARP1 inhibitors. We found that (1) both IR treatment and transient expression of small peptide tr-BRCA1 induce cytoplasmic translocation of BRCA1 protein and subsequent transient inhibition of HR-mediated repair of DSBs in human breast cancer cells in vivo and in mouse tumor model; (2) importantly, we demonstrated that this transient tBRCA1 cytosolic translocation and suppression of repair of DSB correlated with the significantly increased cytotoxic response of breast cancer cells to PARP1 inhibition in vitro. We are still in the processes of verify this important findings in vivo tumor models; (3) finally, p53 status, which controls BRCA1 translocation in response to IR also plays important role in IR-induced sensitization of breast cancer cells to PARP1 inhibition.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2010
- Accession Number
- ADA536445
Entities
People
- Fen Xia
Organizations
- Vanderbilt University