Roles of Synthetic Viability in Breast Cancer Development and Therapy
Abstract
In brief, our study is designed to validate new genetic biomarkers for targeted therapy and identify their roles in breast cancer development, especially among the 30%-50% of triple-negative breast cancers whose genetic contributors have not been identified. We fully expect that it will make significant contribution to the understanding of a large subset of breast cancers and have meaningful impact on the welfare of the patients: about 33% overall patients including ~49% of triple-negative breast cancers. Background of the Study: Triple-negative breast cancers are generally aggressive, mainly affect younger patients, and account for about 15% of all breast cancers. In some ethnic groups such as in African Americans, they account for more than 30% of all breast cancers. Accordingly, an intense effort has been directed to identify the molecular etiology of this type of cancer in order to design more effective molecularly targeted therapy. It is now understood that about 50% of the triple-negative breast cancers showcase mutations of two extensively studied tumor suppressor genes called BRCA1 and p53. These tumors are intrinsically defective in a DNA repair process called homologous recombination. The term "BRCAness" has been coined to describe this subset of breast cancer defective in homologous recombination. More importantly, based on the understanding of DNA repair mechanisms, a "synthetic lethality"-based strategy has been designed to treat BRCAness tumors. This has led to the identification of a class of promising drugs called Poly (ADP-ribose) polymerase inhibitors (PARPi) to specifically kill tumor cells that display BRCAness. Current Challenges Facing the Breast Cancer Patient and Researcher Communities: Although the above developments are very promising, there are still several challenges ahead. First, like every molecularly targeted therapy, the right population of patients has to be identified to make the PARPi treatment effective. Several biological factors are critical to select such suitable patients but have not been fully appreciated by our communities. For example, BRCA1 has multiple functions, but not every BRCA1 mutation affects the homologous recombination process. Thus, not all BRCA1 mutant tumors may be sensitive to PARPi and suitable for the treatment. In addition, some of the BRCA1 mutant cancers may also be accompanied by mutations in another gene called 53BP1 (or p53-binding protein 1). The 53BP mutation can rescue the homologous recombination defect through a process called "synthetic viability," rendering the BRCAness tumor resistant to PARPi. Thus, patients with 53BP1 mutations may not be ideal for PARPi treatment. Unfortunately, researchers were not aware of these caveats at first, and some non-suitable patients were included in early PARPi trials. As a result, there were mixed impressions on the effectiveness of PARPi, and this has created a stigma by the public. Second, the molecular etiology of the remaining 50% of triple-negative breast cancers that are not associated with BRCA1 and p53 genes has not been fully understood. It is not clear whether this population of patients is suitable for PARPi treatment. This prohibits the effective treatment planning for these patients. Our Opportunity to Overcome the Challenges: In the last few years, we have been investigating the functions of a new protein in homologous recombination. This protein was originally identified as a BRCA2 and CDKN1A (cyclin-dependent kinase inhibitor 1A) Interacting Protein, and thus designated as BCCIP. Among more than 400 cases of breast cancer, we were excited to discover that ~33% of all breast cancers have lost BCCIP expression. Intriguingly, BCCIP loss is more frequent in triple-negative breast cancers (49%) than in non-triple-negative breast cancers (25%). As a preclinical study, we found >80% of BCCIP-defective mice developed benign breast cancer nodules, and the progression of these
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510462
Entities
People
- Zhiyuan Shen
Organizations
- Rutgers University
- United States Army