All cells, including cancers, must replicate their DNA to divide. DNA replication is not a smooth process, but one filled with stops that must be overcome. The preferred pathway to restart DNA replication is called homologous recombination (HR), which preserves the genetic code. There is a back-up restart pathway called alternative non-homologous end joining (aNHEJ), but this pathway does not always preserve genetic information and can cause chromosomal abnormalities called translocations. These chromosomal translocations can lead to cell death, cell aging, or transformation to malignancy.

Normal cells express a small RNA segment termed miR223-3p that represses aNHEJ and promotes HR. When a...

Read More

All cells, including cancers, must replicate their DNA to divide. DNA replication is not a smooth process, but one filled with stops that must be overcome. The preferred pathway to restart DNA replication is called homologous recombination (HR), which preserves the genetic code. There is a back-up restart pathway called alternative non-homologous end joining (aNHEJ), but this pathway does not always preserve genetic information and can cause chromosomal abnormalities called translocations. These chromosomal translocations can lead to cell death, cell aging, or transformation to malignancy.

Normal cells express a small RNA segment termed miR223-3p that represses aNHEJ and promotes HR. When a cell is faced with a large amount of DNA damage, say from radiation that would cause DNA replication to stall, normal cells repress miR223-3p so that both aNHEJ and HR DNA repair pathways can be mobilized. However, cells from patients with inherited predisposition to breast or ovarian cancer from BRCA1 mutations cannot use the HR pathway because BRCA1 is required for that HR pathway. Thus, BRCA1-mutant cells require the aNHEJ pathway to replicate, and these cells always repress miR223-3p.

If miR223-3p was present, it would prevent BRCA1-mutant cells from ever replicating. In fact, when we studied a large cohort of breast cancer patients, we found that breast cancer patients that had mutant BRCA1 and repressed miR223-3p had a significantly worse survival. Strikingly, when we added miR223-3p back into BRCA1-mutant cancer cells, there was almost total cell death, indicating that this might be a novel therapeutic agent in these cancers. Thus, we believe that miR223-3p is a key suppressor of transformation to malignancy in breast cells with mutated BRCA1. In this study, we will investigate how BRCA1-mutant cells repress miR223-3p expression and whether that repression is important for cancer formation in mice that lack all BRCA1 in their normal breast cells.

Read Less