Pathology - Theses
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ItemIntegrin β3 as a therapeutic target for breast cancer metastasis to bone( 2011)Breast cancer is the most common cancer in women, with patients currently having high survival rates if the disease is confined to the breast. However, these survival rates drop drastically if the cancer has metastasised to distant sites. Previous studies have shown both tumour and stromal integrin β3 are involved in breast cancer metastasis, yet questions remain regarding its specific role in the process. In particular, whether integrin β3 is essential for metastasis and if so, to which organ and at which stage of the metastatic cascade it is required. Furthermore, the relative contribution of stromal and tumour integrin β3 in tumour growth and metastasis needs to be clarified. To address these questions, the transplantable 4T1 model of breast cancer with spontaneous metastasis was utilised. RNA interference was used to suppress tumour integrin β3 expression in the highly metastatic 4T1.2 and 4T1BM2 cells, and investigate whether tumour integrin β3 is essential for metastasis. Additionally, the contribution of stromal cell populations expressing integrin β3 was investigated in integrin β3 knockout mice. Lastly, the therapeutic potential of targeting integrin β3 was investigated using the disintegrin DisBa-01. Downregulation of tumour integrin β3 expression induced a coordinated decrease in the surface level of the integrin αv subunit. Functional assays revealed integrin αvβ3 dependent decreases in adhesion, migration and MMP9 secretion. In vivo, downregulation of integrin αvβ3 had no affect on primary tumour growth, but significantly reduced spontaneous metastasis to bone, lung and other soft tissues, indicating integrin β3 is required for metastasis to multiple sites. Surprisingly, unlike studies in other tumour types, integrin β3 suppression in 4T1.2 cells did not impact on experimental breast cancer metastasis to lung or bone, suggesting it is acting at an early stage of metastasis. Unlike reports in other models, primary tumour growth was not affected by the loss of stromal integrin β3, indicating orthotopic growth of breast tumours is not dependent on the expression of integrin β3 in stromal cell populations. However, metastasis to bone, but not lung, was reduced in integrin β3 null mice. These observations allow the reconciliation of previous studies that reported conflicting conclusions with regard to the role of stromal integrin β3 in tumour growth and metastasis. In vitro treatment of 4T1BM2 cells with DisBa-01 achieved similar results to down-regulation of the protein by shRNA, suppressing integrin αvβ3 dependent adhesion, proliferation, migration and MMP9 secretion. Unfortunately, these promising results did not translate to effects on tumour growth and metastasis in vivo, and neither experimental nor spontaneous metastasis were suppressed by DisBa-01 treatment under the conditions tested. However, the results obtained provide valuable information with regards to future protocol design. This study demonstrates that tumour expressed integrin β3 is essential for spontaneous breast cancer metastasis to multiple organs, and provides evidence the protein acts at an early stage in the process. It also supports the role of stromal integrin β3 in metastasis to bone, but not to lung. Taken together, these data suggest both tumour and stromal integrin β3 are potential therapeutic targets, with tumour integrin β3 contributing to the process to a greater degree.