Breast cancer is the most common cancer in the UK, but despite recent encouraging increases in survival rates, is still the second most common cause of cancer death in women in the UK. To try to reduce systemic toxicity during treatment of cancer patients, a plethora of targeted therapies are in various stages of development. PARP inhibitors have been shown to be particularly effective in BRCA-deficient cells, making them a contender as a personalised therapy. One of the challenges for targeted therapies is that of resistance, which limits the extent of benefit to the patient. The work described in this study continues previous work within our laboratory, investigating the PARP inhibitor olaparib in a conditional mouse model of BRCA2-mutated human breast cancer. The data presented here establish a correlation between histological tumour type and response to olaparib therapy, with poor responders classified exclusively as mesenchymal-like metaplastic spindle cell carcinomas (MSCC). This suggests that further patient stratification is required when deciding on whether this therapy may be suitable, and may explain why not all patients with BRCAmutated breast cancer have benefitted from olaparib therapy in current clinical trials. Investigation of olaparib resistance in this study indicated that several currently proposed mechanisms of resistance were not pertinent to the Brca2/p53 model, hence novel mechanisms were sought. Histopathological analysis of resistant tumours showed that the majority were MSCCs, representing a significant change in the proportion compared to an untreated cohort. Other resistant tumour types had epithelial morphology, but showed an increase in expression in some mesenchymal-like genes compared to untreated cohorts, suggesting that mesenchymal features may be important in causing resistance to olaparib. A similar tumour model, incorporating the additional deletion of E-cadherin, was used to investigate whether lack of this protein in tumours affected response and resistance to olaparib therapy. Loss of Cdh1 led to an increase in invasive ductal carcinomas of no special type (IDC-NST) and the absence of MSCCs, suggesting that genetic loss of expression does not drive the formation of mesenchymal-like tumours. Correlating with this, loss of E-cadherin did not drive epithelial-to-mesenchymal transition in these tumours and had no effect on response to olaparib therapy or resistance to the inhibitor. Taken together, the data presented in this thesis suggest that MSCCs have an intrinsic resistance to olaparib therapy, and tumours which initially respond to olaparib therapy harness or acquire certain mesenchymal characteristics in order to develop resistance during treatment.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:633557 |
| Date | January 2014 |
| Creators | Ordonez, Liliana |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/68611/ |
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