Pathology - Theses
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ItemThe contribution of stromal caveolin-1 to breast cancer metastasis( 2012)In a previous study, our group has shown that the expression of caveolin-1 (CAV1) in normal tissue surrounding a primary breast cancer is a powerful prognostic indicator of subsequent metastatic disease. While reports linking expression of CAV1 within breast tumour cells to clinical outcome have not led to any clear conclusions, the finding of a strong positive correlation between loss of CAV1 expression in breast tumour stroma and poor prognosis by our group and others, is novel and exciting as it offers the potential of a reliable prognostic indicator of metastatic disease. These clinical observations have led us to propose the hypothesis that breast tumour cells decrease stromal CAV1 expression, and a reduction in stromal CAV1 expression leads to promotion of tumour growth and metastasis. The aims of this project were to model the progression in breast cancer following stromal CAV1 loss, and determine the underlying breast tumour-stroma paracrine metastasis. Tumours arising from weakly metastatic mammary cell lines 66cl4 and 4T1ch5, grow at a faster or similar rate respectively, when co-injected with CAV1 null mammary fibroblasts. In contrast, co-injection with CAV1 expressing mammary fibroblasts has a suppressive effect on tumour growth. Metastasis to lung was significantly higher in mice with resected primary tumours that arose from co-inoculation of 4T1ch5 cells and CAV1 null mammary fibroblasts, in addition to a significant increase in individual lung tumour nodule size. However no significant difference in immune infiltrate in these resected tumours was observed in preliminary flow cytometry analysis. No significant differences in primary tumour growth or metastasis were observed in human xenograft models. To mimic the phenotype observed in vivo, 3D co-culture assays were developed. Although these assays demonstrated a positive effect of fibroblasts on tumour cell invasion and proliferation, no stromal CAV1 specific effect was observed in response to fibroblast co-culture or conditioned medium. To further understand the consequences of the loss of stromal CAV1, profiling of CAV1 expressing and null mouse mammary fibroblasts was conducted using cytokine arrays and cDNA microarrays. A significant increase in Gas6 and a decrease in RANTES cytokine secretion were observed as a result of CAV1 loss, with no significant changes in their transcript levels. In summary, results from this project demonstrate that stromal CAV1 is an important prognostic factor in breast cancer progression. Based on these findings, a stromal targeted therapy to that restores or substitutes for CAV1 activity in stromal cells, or that targets CAV1 regulated cytokines such as Gas6, may be a viable therapy in the treatment of breast cancer metastasis.