Boone, J.J.M.; (2007) The role of ErbB2 and BRCA1 in repair of drug-induced DNA damage. Doctoral thesis , University of London.

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Abstract

Breast cancer is the most common cause of cancer in women. Overexpression of ErbB2 (HER2) occurs in 25-30% of sporadic breast cancer and is associated with poor prognosis. New therapies targeting ErbB2 have been developed and shown to influence the activity of chemotherapeutic agents. The main aim of this investigation was to study the potential role of ErbB2 in the repair of drug-induced DNA damage. Synergistic effects of trastuzumab, a monoclonal anti-ErbB2 antibody, in combination with common chemotherapeutics were evaluated in cell lines expressing different level of ErbB2. In addition, effects of ErbB2 nuclear localisation on cisplatin sensitivity were also investigated. Using the comet assay, effects of ErbB2 expression and its nuclear translocation on the kinetic of damage and repair of DNA interstrand crosslinks and DNA strand breaks were examined. Effects of trastuzumab, alone and in combination with cisplatin, on the cell cycle and apoptosis were studied using FACS analysis. Trastuzumab was shown to enhance drug sensitivity in cell lines overexpressing ErbB2. ErbB2 overexpression caused increased resistance to cisplatin whereas deletion of its nuclear localisation signal sequence led to an increased sensitivity. Study of the repair of drug-induced DNA damage revealed that modulation of ErbB2 expression altered the kinetics of repair of cisplatin-induced DNA interstrand crosslinks but not DNA intrastrand crosslinks, and that ErbB2 nuclear translocation was important for the repair of cisplatin DNA damage. BRCA1 is another important protein, as germline mutations of this gene have been shown to substantially increase the risk of hereditary breast cancer. Sensitivity of BRCA1 down-regulated cells to radiotherapy, chemotherapeutic agents alone and in combination with gefitinib, an EGFR tyrosine kinase inhibitor, was also evaluated. Study of BRCA1 down-regulation produced conflicting results with published data but a synergistic effect was obtained between cisplatin and gefitinib in cells with down-regulated BRCA1 expression. These results establish a link between nuclear ErbB2 and repair of drug-induced DNA damage. In addition, they suggest an interaction between BRCA1 and the EGFR signalling pathway in cisplatin-induced DNA damage repair.

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