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The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
Departmen of Oncology, Karolinska University Hospital, Stockholm, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
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.

Place, publisher, year, edition, pages
2007. Vol. 84, no 3, 242-251 p.
Keyword [en]
Radiotherapy; Breast cancer; BRCA1; BRCA2; Rad51
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-17953DOI: 10.1016/j.radonc.2007.06.012OAI: oai:DiVA.org:liu-17953DiVA: diva2:213081
Available from: 2009-04-27 Created: 2009-04-27 Last updated: 2017-12-13Bibliographically approved
In thesis
1. DNA repair pathways and the effect of radiotherapy in breast cancer
Open this publication in new window or tab >>DNA repair pathways and the effect of radiotherapy in breast cancer
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:nbn:se:liu:diva-17955 (URN)978-91-7393-668-2 (ISBN)
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

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Söderlund, KarinStenmark Askmalm, Marie

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