Inheritance of mutations in one of the breast cancer susceptibility genes, BRCA1 or BRCA2, is the most significant risk factor for developing breast cancer. BRCA1 and BRCA2 are known to function in a common DNA repair pathway, named homologous recombination (HR). HR is an essential DNA repair process that uses the homologous sister chromatid to carry out accurate repair of DNA double-strand breaks (DSBs), predominantly taking place during S and G2 phases of the cell cycle. However, while BRCA1 and BRCA2 are frequently mutated in familial breast cancers, mutations of these tumor suppressors are rare in sporadic breast cancers, raising the possibility that other genes involved in HR repair pathway, but not BRCA1 or BRCA2, may be mutated or dysregulated in sporadic breast cancers. In fact, HR deficiencies are frequently present in sporadic breast cancers (defined as a BRCAness or BRCA-like profile). To better understand the function of HR defects in sporadic breast cancer development, we have to know more about HR pathway by identifying novel HR factors other than the known BRCA1 and BRCA2 tumor suppressors. The BRCA2-interacting protein, RAD51, is at the center of HR pathway. This proposed project focuses on identifying a set of new RAD51-associated HR factors, including FIGNL1, KIAA0146 and C1orf112, and testing their potential roles in breast cancer development and treatment.
The specific aims are:
Aim 1 : Elucidate the molecular functions of FIGNL1 protein complex in HR repair;
Aim 2 : Evaluate the functions of FIGNL1 in tumorigenesis;
Aim 3 : Determine the potential roles of FIGNL1 protein complex in breast cancer development and therapy. The proposed study is expected to identify novel factors involved in HR repair and generate important knowledge for understanding breast cancer etiology, which may have great implications for the clinical management of breast cancer patients.

Public Health Relevance

The well-known breast cancer susceptibility genes BRCA1 and BRCA2 encode DNA repair factors acting in a common DNA repair pathway termed homologous recombination (HR). HR deficiency is often associated with drug sensitivity in cancer patients and is now being specifically targeted for the development of new anticancer agents. Our research is expected to identify novel factors involved in HR repair and breast cancer development, which will allow the development of better strategies for the prevention and treatment of breast cancer and therefore reduce the incidence and mortality of breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K22)
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Special Emphasis Panel (ZCA1)
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Jakowlew, Sonia B
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Lee, Yuan-Cho; Zhou, Qing; Chen, Junjie et al. (2016) RPA-Binding Protein ETAA1 Is an ATR Activator Involved in DNA Replication Stress Response. Curr Biol 26:3257-3268