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DNA repair pathways and the effect of radiotherapy in breast cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 84 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1112
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-17955ISBN: 978-91-7393-668-2 (print)OAI: oai:DiVA.org:liu-17955DiVA: diva2:213090
Public defence
2009-05-20, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-05-07 Created: 2009-04-27 Last updated: 2009-08-21Bibliographically approved
List of papers
1. Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells
Open this publication in new window or tab >>Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells
2005 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 26, no 1, 25-32 p.Article in journal (Refereed) Published
Abstract [en]

Radiotherapy is widely used in the treatment of breast cancer and reduces the risk of loco-regional recurrence. Overexpression of the erbB2 receptor occurs in 20-30% of all breast cancers, and seems to be involved in chemotherapeutic resistance of breast cancer cells and radioresistance of lung cancer cells. The hypothesis of this study was that erbB2 confers resistance to radiation-induced apoptosis in breast cancer cells through the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway. Two human breast cancer cell lines were used, BT-474 and MCF-7. BT-474 cells overexpress erbB2 and have mutated p53, while MCF-7 have normal expression of erbB2 and functional p53. The cells were treated with the PI3-K inhibitor wortmannin or the erbB receptor ligand heregulin-ß1, which is expressed by both malignant and stromal cells in vivo. After pharmacological treatment, the cells were irradiated with 10 Gy gamma-radiation. Consistent with the p53 status in the cell lines, gamma-radiation caused G1 arrest in MCF-7 cells, but not in BT-474 cells. 10 Gy gamma-radiation increased apoptosis by on an average 76% (95% CI, 44-109%) in MCF-7. Treatment of MCF-7 with heregulin-ß1 decreased apoptosis by 66% (95% CI, 48-84%) compared to the untreated controls. In BT-474 cells, wortmannin in combination with radiation resulted in 119% (95% CI, 76-161%) more apoptosis compared to wortmannin alone, whereas radiation alone resulted in 45% (95% CI, 15-75%) increased apoptosis. This radiosensitising effect was not seen in MCF-7. Furthermore, transfection of MCF-7 cells with constitutively active Akt made the cells more resistant against apoptosis. Taken together, our results support the hypothesis that the erbB2/PI3-K/Akt signalling pathway is involved in resistance to radiation-induced apoptosis in breast cancer cells in which this signalling pathway is overstimulated.

Keyword
HER2/neu, erbB2, protein kinase B, Akt, ionising radiation, apoptosis, breast cancer
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17951 (URN)
Available from: 2009-04-27 Created: 2009-04-27 Last updated: 2017-12-13Bibliographically approved
2. Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer
Open this publication in new window or tab >>Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer
Show others...
2007 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 68, no 1, 50-58 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Post-operative radiotherapy is offered to a majority of breast cancer patients, since it significantly reduces the risk of local recurrence. However, some patients still develop recurrences. Owing to their vital roles in the repair of radiation-induced double-strand breaks, the Mre11/Rad50/Nbs1 (MRN) complex and the ATM protein might be implicated in tumour cell resistance to radiotherapy. The aim of this study was to investigate the expression and predictive role of these DNA repair proteins for the outcome of radiotherapy in breast cancer patients.

Patients and Methods: The protein expression of ATM and the proteins in the MRN complex were investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (CMF).

Results: Compared to normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1 and ATM was reduced in a majority of the tumours. Weak expression of the MRN complex was correlated to high histological grade and ER negativity (p=0.01 and p=0.0001). Radiotherapy significantly reduced the risk of local recurrence as compared to chemotherapy (p=0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (RR=0.27, 95% C.I. 0.098-0.72, p=0.009), whereas patients with negative/weak MRN had no benefit of radiotherapy compared to CMF. These results suggest that an intact MRN complex is important for the tumour cell eradicating effect of radiotherapy.

Keyword
Radiotherapy, breast cancer, mre11, rad50, nbs1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17952 (URN)10.1016/j.ijrobp.2006.12.005 (DOI)
Available from: 2009-04-27 Created: 2009-04-27 Last updated: 2017-12-13Bibliographically approved
3. The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer
Open this publication in new window or tab >>The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer
2007 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 84, no 3, 242-251 p.Article in journal (Refereed) Published
Abstract [en]

Background and Purpose: The breast cancer susceptibility genes BRCA1 and BRCA2 interact with Rad51, one of the central components in the homologous recombination repair pathway. This study evaluates the prognostic and predictive role of BRCA1, BRCA2 and Rad51, individually and as a complex, in breast cancer.

Material and Methods: Expression of BRCA1, BRCA2 and Rad51 was investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive postoperative radiotherapy or adjuvant chemotherapy (CMF).

Results: 53% (112/212) of the tumours had reduced expression of the BRCA1/BRCA2/Rad51 complex. Low expression correlated to high histologic grade (p=0.05). Patients with low expression of the complex developed significantly more local recurrences as compared to patients with high expression (RR=3.20, 95% C.I. 1.48-6.88, p=0.003). Expression of the BRCA1/BRCA2/Rad51 complex was an independent prognostic factor in multivariate analysis (p=0.03). Patients with low expression of the complex responded well to radiotherapy (RR=0.31, 95% C.I. 0.14-0.70, p=0.005), whereas patients with high expression had few local recurrences and no additional benefit from radiotherapy (RR=1.08, 95% C.I. 0.40-2.90, p=0.88).

Conclusions: Low expression of the BRCA1/BRCA2/Rad51 complex is a marker of poor prognosis, but predicts good effect of radiotherapy in patients with early breast cancer.

Keyword
Radiotherapy; Breast cancer; BRCA1; BRCA2; Rad51
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17953 (URN)10.1016/j.radonc.2007.06.012 (DOI)
Available from: 2009-04-27 Created: 2009-04-27 Last updated: 2017-12-13Bibliographically approved
4. The RAD51 135G/C polymorphism is related to the effect of adjuvant therapy in early breast cancer
Open this publication in new window or tab >>The RAD51 135G/C polymorphism is related to the effect of adjuvant therapy in early breast cancer
2015 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 141, no 5, 797-804 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: A single-nucleotide polymorphism, RAD51 135G/C, in the untranslated region of the RAD51 gene has been found to elevate breast cancer risk among BRCA2 carriers. The purpose of this study was to investigate if this polymorphism is related to RAD51 protein expression, prognosis of early breast cancer and if it contributes to resistance to radiotherapy or cyclophosphamide/5-fluorouracil/methotrexate (CMF) chemotherapy.

Methods: We genotyped 306 patients with early breast cancer, who were randomised to receive post-operative radiotherapy or CMF chemotherapy, for the RAD51 135G/C polymorphism. Expression of RAD51 protein was evaluated with immunohistochemistry.

Results: The frequency of C-allele was 15.4% (including three C/C homozygotes). There was no correlation between genotype and protein expression pattern in tumours. Patients who were homozygous for the wildtype G/G genotype had a significant benefit of radiotherapy (RR=0.32, 95% C.I. 0.16-0.64, p=0.001). CMF chemotherapy significantly reduced the risk of distant recurrence during the first 20 years in patients who had the C-allele (RR=0.29, 95% C.I. 0.10-0.88, p=0.03), whereas patients who were G/G homozygotes had no benefit from chemotherapy over radiotherapy (RR=1.09, 95% C.I. 0.77-1.6, p=0.61). There was a significant interaction between chemotherapy and genotype (p=0.02). Genotype was not related to the rate of distant recurrence among patients treated with radiotherapy.

Conclusion: Breast cancer patients who were homozygous for the wildtype G allele had a significant benefit of radiotherapy. The results suggest that the RAD51 135G/C polymorphism predicts the effect of CMF chemotherapy in early breast cancer.

Place, publisher, year, edition, pages
Springer Publishing Company, 2015
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17954 (URN)10.1007/s00432-014-1859-0 (DOI)000352859700003 ()
Available from: 2009-04-27 Created: 2009-04-27 Last updated: 2017-12-13Bibliographically approved

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