Date of Award
Doctor of Philosophy (PhD)
Dr. William J. Muller
Experimental and clinical evidence implicate the β-integrin subunit and its associated intracellular effector ILK in the initiation and progression of human breast cancer. Roles for these proteins in promoting the oncogenic process, however, have not been demonstrated in vivo. As a result, experiments were designed to test the tumour-promoting properties of β-integrin and ILK in the mammary glands of transgenic mice. The first of these experiments involved the targeted ablation of a conditional allele of β-integrin in a transgenic mouse model of human breast cancer. Using this approach, it was found that the expression of β-integrin is required for oncogeneinduced transformation of the mammary gland epithelium in vivo. This requirement for β1-integrin expression was observed during both the initiation of tumourigenesis, as well as for maintaining the growth of established tumours. In addition, a block in tumour cell proliferation following ablation of β1-integrin expression was found to be associated with the suppression of F AK autophosphorylation, providing a molecular mechanism underlying the requirement for β1-integrin expression during tumourigenesis. The second experiment was designed to test the oncogenic properties of ILK, through the establishment of transgenic mice overexpressing ILK in the mammary gland epithelium. Following the induction of a hyperplastic mammary gland phenotype, these mice developed solid mammary tumours showing evidence of epithelial-to-mesenchymal transition, confirming that ILK overexpression can contribute to mammary tumourigenesis in vivo. Since expression of both β-integrin and ILK have been reported in samples of aggressive human tumours, these results may have clinical significance to the treatment of human breast malignancies.
White, Donald E., "The role of β-integrin signaling in mammary gland tumourigenesis" (2004). Open Access Dissertations and Theses. Paper 1545.