Pathology - Theses
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ItemInvestigating breast cancer metastasis to brain in pre-clinical mouse models of metastasis( 2015)An increasing number of advanced breast cancer patients develop overt brain metastases. This is partly due to recent advances in therapies for visceral metastases that extend life of patients but remain largely ineffective against late stage brain metastases. Among the subtypes of breast cancer, triple negative breast cancer (TNBC) is particularly aggressive and has a strong propensity to metastasise to the brain. Although TNBC are initially sensitive to chemotherapy (Keam et al., 2007), response to treatment is usually limited by the development of resistance. Moreover, current endocrine or human epidermal growth factor receptor 2 (HER2)-targeting therapies are not effective against TNBC due to the absence of estrogen receptor (ER), progesterone receptor (PR) or HER2 receptor in this tumour subtype. Unfortunately, the limited availability of mouse models that closely recapitulate the entire metastatic process from the mammary gland to the brain remains a major barrier to identifying relevant prognostic/therapeutic target genes or testing novel therapies against TNBC brain metastases under clinically relevant settings. Thus, the first aim of this project was to develop a clinically relevant and robust mouse model of breast cancer brain metastasis (4T1Br4) that gives rise to a high incidence of spontaneous brain metastases in syngeneic/immune competent animals. Phenotypic, functional and transcriptomic characterisation showed that the 4T1Br4 model is phenotypically, functionally and genetically relevant to human brain-metastatic TNBC. In particular, we found that 4T1Br4 cells are highly migratory, are more adhesive to brain-derived endothelial cells and have increased ability to transmigrate endothelial cells and invade in response to brain-derived factors compared to the parental 4T1 cells from which they are derived. We identified a cell adhesion molecule, limitrin, whose high expression is associated with the increased brain metastatic abilities of 4T1Br4 tumours. Prognostic analysis of limitrin using BreastMark analysis tool revealed that limitrin is associated with metastasis and poor clinical outcome in basal-like but not other subtypes of breast cancer. In addition, we found that limitrin promotes trans-endothelial migration in vitro, a function likely to be critical for the crossing of tumour cells through the blood-brain barrier (BBB). Lastly, we tested the efficacy of novel histone deacetylase inhibitors (HDACi) namely SB939 and 1179.4b, against mouse (4T1Br4) and human (MDA-MB-231Br) brain metastatic breast cancer cell lines. SB939 and 1179.4b potently inhibited proliferation and survival of both cell lines in vitro and inhibited 4T1Br4 tumour growth and spontaneous metastasis to bone and brain in vivo. Moreover, we observed that both HDACi have radiosensitising properties against both cell lines in vitro. In summary, we developed a clinically relevant mouse model of spontaneous TNBC brain metastasis amenable to identifying therapeutic/prognostic target genes and evaluating novel therapies against this incurable disease.