An analysis of the role of fibroblasts in the promotion of breast cancer invasion
There is increasing evidence that stromal fibroblasts promote breast cancer invasion. This thesis aimed to dissect phenotypic and genotypic differences between fibroblasts from normal donors and patients with breast cancer and to relate these to their capacity to promote tumour cell invasion.;Immunohistochemical analysis demonstrated up-regulation of alpha4 integrin, alphavbeta3 integrin and alpha-SMA in peri-tumoural fibroblasts compared to normal fibroblasts in vivo.;Primary isolated peri-tumoural fibroblasts demonstrated greater invasion promoting capacity (IPC) than normal breast fibroblasts, however, matched non-breast (dermal) fibroblasts from patients with breast cancer also exhibited higher (IPC) than dermal fibroblasts from normal donors implying that intrinsic genetic differences exist.;Since fibroblast derived matrix metalloproteinases (MMP's) are known to contribute to tumour invasion, fibroblast IPC was related to expression levels and release of MMP's. No significant difference in MMP expression, as measured by real time PCR, was detected between normal and tumour donors. However, a trend towards higher levels of MMP release and IPC of fibroblasts populations was observed.;Functional promoter polymorphisms have been shown to influence expression of some MMPs. This thesis demonstrated a trend towards increased frequency of the high expression MMP-3 5A allele and both the tumour group and high IPC fibroblasts. In addition the 5A allele correlated with increased levels of MMP-3 release.;Furthermore, regulation of fibroblast IPC and MMP-3 release was shown to be co-ordinately regulated by alpha and alpha5 integrins.;In conclusion, this thesis demonstrates phenotypic differences between fibroblasts isolated from normal donors and patients with breast cancer which influence their capacity to promote tumour invasion. Also intrinsic genetic differences exist between patients which relate to both IPC and MMP release.