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Khirwadkar, Yamini Jayant
Languages: English
Types: Doctoral thesis
The pure anti-oestrogen faslodex presents a valuable therapeutic option for post-menopausal women with endocrine-sensitive advanced breast cancer. However, emergence of resistance following long-term treatment constitutes a major clinical problem as faslodex-refractory disease is associated with poor prognosis. Consequently, elucidation of the mechanisms underlying resistance is imperative. An in vitro MCF-7 cell model of acquired resistance to faslodex (FAS-R) has been developed in our laboratory. Previous studies using this model revealed endocrine insensitivity to be accompanied by development of an invasive phenotype. Since proteolytic degradation of extracellular matrix components by matrix metalloproteinases (MMPs) is a prerequisite for tumour invasion and metastasis, the objective of this project was to explore the role of these proteases and tissue inhibitors of matrix metalloproteinases (TIMPs) hi the aggressive behaviour of faslodex-resistant breast cancer cells. Additional studies were performed to identify the dominant growth factor signalling pathway regulating these pro-invasive events. MMP and TIMP mRNA expression in FAS-R cells was variable. MMP-2 mRNA was increased in FAS-R cells compared with WTMCF-7 cells. Significantly, treatment with a broad-spectrum MMP inhibitor significantly reduced the invasive behaviour of FAS-R cells suggesting a central role for. MMPs in FAS-R invasion. Importantly, FAS-R cells were found to overexpress c-Met receptor tyrosine kinase which, when activated by HGF/SF, induced latent MMP-9 protein expression and considerably augmented the motile, migratory and invasive capacities of these cells. Both ERK1/2 and PI3K/AKT pathways were activated by HGF/SF, and signalling through both resulted in increased secretion of latent MMP-9 protein. However, HGF/SF-enhanced FAS-R cell invasion was only suppressed by inhibition of the PI3K/AKT pathway or following treatment with the MMP inhibitor. Collectively, these data suggest that in FAS-R cells HGF/SF/c-Met signalling enhances aggressive behaviour via PI3K-mediated MMP-9 secretion. c-Met may therefore present a therapeutic target in faslodex resistance.
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