Figure 4.

A model depicting BRCA1 associated tumorigenesis in regarding to the development of PARP resistance. In familial cancer, one mutant BRCA1 allele is inherited from the germline. One additional mutation in the BRCA1 locus (LOH) results in a BRCA1 deficiency, which could result in genetic instability, activation of p53-dependent cell cycle checkpoints and apoptosis pathways, leading to growth arrest and cell death. However, genetic instability triggered by BRCA1 loss could facilitate mutations in general. When permissive mutations, such as ATM, CHK2 or p53 heterozygous or homozygous mutations, occur, BRCA1-/- cells survive. Cells in this phase may be sensitive to PARP inhibition. However, PARP resistance may develop when further genetic alterations occur leading to full growth of breast cancers.