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- W2016324097 abstract "AbstractBreast cancer is the most common cancer in the UK today, with incidence ratesrising steadily. Prognosis is improving but patients with metastatic disease onlyhave a 15% chance of surviving 5 years beyond prognosis. Therefore, factorsinfluencing the metastatic spread of breast cancer require better understanding.The matrix metalloproteinases (MMPs) are a family of proteases thought topromote metastasis due to their matrix degradation capabilities. MMP-8however has been discovered to be anti-tumourigenic in many cancers, andanti-metastatic in breast cancer. This occurs through unknown mechanisms, sothis work sought to gain further insight into the functional effects of MMP-8. Inthe literature it has been suggested that MMP-8 is tumour protective through itsrole in regulating innate immune responses and preventing chronicinflammation. This occurs through activational cleavage of a pro-inflammatorychemokine, Interleukin-8 (IL-8).Using an in vitro over-expression model it is shown in this thesis that MMP-8reduced 2D random migration and scratch wound closure. It also increased celladhesion and reduced colony formation and prevented primary tumour growthin mice. These data indicate an anti-tumourigenic role for MMP-8.Biochemically, MMP-8 induced expression of IL-8 in mammary carcinoma cells,and also the expression of a pro-inflammatory cytokine IL-6, dependent on itscatalytic activity. This required NFĸB signalling and IL-6 also required ProteaseActivated receptor-2. This occurred following transient expression of MMP-8,and also in rare stably transfected clones that expressed MMP-8 long-term.However, wild-type MMP-8 was not tolerated by breast cancer cells and wasepigenetically silenced, potentially as a mechanism to overcome growthinhibitory effects exerted by wild-type MMP-8. In these rare “long-term” MMP-8expressing cells phenotypic alterations occurred, including elevated IL-6 and IL-8 expression independent of MMP-8, and a self-reinforcing loop between MMP-8, IL-6 and IL-8.3This pathway may contribute to the anti-tumourigenic and metastasissuppressive effects of MMP-8, or it may represent a cellular response toovercome the anti-tumour actions of the protease." @default.
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- W2016324097 date "2013-04-01" @default.
- W2016324097 modified "2023-09-27" @default.
- W2016324097 title "Investigation of the functions of matrix metalloproteinase-8 (MMP-8) in mammary carcinoma cells" @default.
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