Investigation of the functions of Matrix Metalloproteinase-8 (MMP-8) in Mammary Carcinoma Cells

Thirkettle, Sally (2013) Investigation of the functions of Matrix Metalloproteinase-8 (MMP-8) in Mammary Carcinoma Cells. Doctoral thesis, University of East Anglia.

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Breast cancer is the most common cancer in the UK today, with incidence rates
rising steadily. Prognosis is improving but patients with metastatic disease only
have a 15% chance of surviving 5 years beyond prognosis. Therefore, factors
influencing the metastatic spread of breast cancer require better understanding.
The matrix metalloproteinases (MMPs) are a family of proteases thought to
promote metastasis due to their matrix degradation capabilities. MMP-8
however has been discovered to be anti-tumourigenic in many cancers, and
anti-metastatic in breast cancer. This occurs through unknown mechanisms, so
this work sought to gain further insight into the functional effects of MMP-8. In
the literature it has been suggested that MMP-8 is tumour protective through its
role in regulating innate immune responses and preventing chronic
inflammation. This occurs through activational cleavage of a pro-inflammatory
chemokine, Interleukin-8 (IL-8).
Using an in vitro over-expression model it is shown in this thesis that MMP-8
reduced 2D random migration and scratch wound closure. It also increased cell
adhesion and reduced colony formation and prevented primary tumour growth
in 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 its
catalytic activity. This required NFĸB signalling and IL-6 also required Protease
Activated 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 was
epigenetically silenced, potentially as a mechanism to overcome growth
inhibitory effects exerted by wild-type MMP-8. In these rare “long-term” MMP-8
expressing 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.
This pathway may contribute to the anti-tumourigenic and metastasis
suppressive effects of MMP-8, or it may represent a cellular response to
overcome the anti-tumour actions of the protease.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Users 2259 not found.
Date Deposited: 05 Mar 2014 11:41
Last Modified: 05 Mar 2014 11:41

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