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…
Contents
Introduction
Importance
Breast cancer
Risk factors
Prognosis versus prediction of treatment outcome
Breast cancer tumour biology
Tumour suppressors versus oncogenes
Tumour heterogeneity
Breast cancer treatment
Surgery, chemotherapy and endocrine treatment
Radiotherapy
Biological effects of ionising radiation
Radiation-induced DNA damage
viiCellular response to ionising radiation
Cell cycle arrest
Cell death
Repair of radiation-induced damages
Tumour cell resistance to ionising radiation
HER2 and AKT signalling in breast cancer
The HER2 receptor
Role in breast cancer
The PI3-K/AKT signalling pathway
Connections between AKT signalling and DNA repair
DNA repair pathways as targets for cancer therapy
Aims of the thesis
General aim
Specific aims
Comments on materials and methods
Cell culture
Patients and tumour material
Western blot
Cell cycle analysis by flow cytometry
Apoptosis detection
Immunohistochemistry
TMA
Antibodies
Fixation and antigen retrieval
Advantages and disadvantages
PCR-RFLP
Statistical analysis
Results & Discussion
HER2/PI3-K/AKT signalling is important for resistance to radiation-induced apoptosis (Paper I)
Cell cycle regulation after γ-radiation
Radiation-induced apoptosis
DNA repair-associated proteins in breast cancer (Paper II and III) 50Reduced or elevated expression of DNA repair proteins in
breast tumours?
Significance of the subcellular localisation
Expression patterns of proteins that form a complex together
Reduced expression of complexes is associated with clinico-
pathological variables
Relation to recurrence-free survival
Can the expression of DNA repair proteins predict the effect
of radiotherapy?
Does a polymorphismin RAD51 influence protein expression, prog-
nosis and the effect of therapy? (Paper IV)
Conclusions
Future perspectives
Acknowledgements
Bibliography
Author: Söderlund Leifler, Karin
Source: Linköping University
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