Imbalance of homologous recombination and DNA replication as a driver of hereditary breast cancer

• Applicants: Professorin Dr. Kerstin Borgmann; Privatdozent Dr. Helmut Pospiech
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology ; Human Genetics
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 336226267

Breast cancer is the most frequently diagnosed cancer in women. Early onset is a hallmark of hereditary predisposition to the disease, and is accompanied by a poor prognosis. Carriers of genes mutated in BRCA1/2, PALB2 and ABRAXAS have a high risk to develop cancer earlier and more often during their lifetime than non-carriers. The commonly accepted model is based on the hypothesis that loss of heterozygosity (LOH) of the functional allele causes this increased and early onset tumorigenesis. However, the work of our groups and others have shown that the delicate interplay between homologous recombination, the regulation of DNA replication, and the DNA damage response is disturbed in cells of hereditary breast cancer mutation carriers. Importantly, these early drivers of genomic instability are the consequence of haploinsufficiency rather than of LOH, even in case of mutations in breast cancer genes that are considered to require LOH for the subsequent onset of cancer. This leads us to consider a new model in which a moderate reduction in the amount of HR proteins is already sufficient to disrupt the functionality of the HR complex during DNA replication and thus drives genomic instability. We will address this hypothesis using primary and cancer cell lines with controllable expression of breast cancer relevant genes as well as lymphoblastoid cells lines from hereditary breast cancer cohorts with heterozygous mutation of the respective genes. The project is broken down into the following work packages:WP1: Only sufficient and balanced expression of HR proteins guarantees functionality of the HR complex.WP2: Appropriate damage signaling, DNA repair and completion of DNA replication depends on the amount of HR proteins.WP3: Insufficient HR causes replication-dependent genomic instability via replication fork breakage or incomplete replication.WP4: Carriers with heterozygous mutations in BRCA1, BRCA2 and ABRAXAS show defects in DNA damage signaling, DNA replication and HR repair. The applied project is a collaborative action of the Laboratory of Radiobiology & Experimental Radiooncology at the University Hospital Hamburg Eppendorf (RO-UKE) and the Leibniz Institute on Aging - Fritz Lipmann Institute Jena (FLI). This provides a unique combination of know-how on DNA repair pathways, replication processes and attenuated damage response as a driver of genomic instability. In addition, this project puts together the clinically orientated approach focused on the translational use of DNA repair in tumor therapy of the RO-UKE with the basic expertise in biochemistry, cell and molecular biology and age-related diseases at the FLI.

• DFG Programme: Research Grants
• International Connection: Finland
• Cooperation Partner: Professor Dr. Robert Winqvist