DNA repair pathways and the effect of radiotherapy in breast cancer

Abstract: A large proportion of breast cancer patients are treated with radiotherapy. Ionising radiation induces different DNA damages, of which double-strand breaks are the most severe. They are mainly repaired by homologous recombination or non-homologous end-joining. Different protein complexes have central roles in these repair processes. In addition to the ability to repair DNA damage, cellular radiosensitivity is also affected by mitogenic signals that stimulate survival and inhibit apoptosis. The phosphatidylinositol 3-kinase (PI3-K)/AKT pathway controls cell proliferation, invasiveness and cell survival. AKT is regulated by upstream growth factor receptors, one of them being HER2 (also called ErbB2). HER2 is overexpressed in 15-30% of all breast cancers and associated with poor prognosis.In this thesis, we have studied factors that affect tumour cell resistance to ionising radiation. In Paper I, the role of HER2/PI3-K/AKT signalling in radiation resistance was investigated in two breast cancer cell lines. The results support the hypothesis that the HER2/PI3-K/AKT pathway is involved in resistance to radiation-induced apoptosis in breast cancer cells in which this signalling pathway is overstimulated.We also investigated if the protein expression of several DNA repair-associated proteins influence the prognosis and treatment response in early breast cancer. Moderate/strong expression of the MRE11/RAD50/NBS1 (MRN) complex predicted good response to radiotherapy, whereas patients with negative/weak MRN had no benefit from radiotherapy as compared to chemotherapy (Paper II). These results suggest that an intact MRNcomplex is important for the tumour-eradicating effect of radiotherapy. In Paper III, low expression of the BRCA1/BRCA2/RAD51 complex was associated with an aggressive phenotype, an increased risk of local recurrence and good response to radiotherapy.In Paper IV, we studied if a single nucleotide polymorphism, RAD51 135G/C, was related to RAD51 protein expression, prognosis and therapy resistance. We found that genotype was not correlated to neither protein expression nor prognosis. Patients who were G/G homozygotes had a significant benefit from radiotherapy. The results also suggested that the RAD51 135G/C polymorphism predicts the effect of chemotherapy in early breast cancer.In conclusion, DNA repair proteins are potential prognostic and predictive markers. The results indicate that proteins in different repair pathways may contribute differently to the effect of radiotherapy. Also, the HER2/PI3-K/AKT signalling pathway protects cells from radiation-induced apoptosis. In the future, it might be possible to target some of these proteins with inhibitory drugs to sensitise tumours to radiotherapy.