The role of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-­‐15 (ADAMTS-­‐15) in Breast Cancer

Kelwick, Richard (2013) The role of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-­‐15 (ADAMTS-­‐15) in Breast Cancer. Doctoral thesis, University of East Anglia.

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Abstract

Breast cancer is the most common cancer in women and in 2008 accounted for
8% of UK cancer related deaths. A poor prognosis is particularly conferred upon
individuals with evidence of metastatic breast cancer. With some studies noting
that at least 70% of patients dying with breast cancer have evidence of
metastatic disease. In order to develop novel therapeutic strategies a greater
understanding of breast cancer tumourigenesis and metastasis is required.
Metalloproteinases were implicated as key drivers of metastasis through their
ability to degrade the components of the extracellular matrix. This perspective is
now superseded with evidence highlighting the involvement of
metalloproteinases in an array of biological roles, from maintaining tissue
homeostasis to angiogenesis, and importantly these roles can have tumour
suppressive effects. Several metalloproteinases from the A Disintegrin and
Metalloproteinase with thrombospondin motifs (ADAMTS) family are candidate
tumour suppressors, including ADAMTS-15. In the context of breast cancer
relatively high levels of ADAMTS-15 expression had previously been associated
with increased relapse free survival. However the functional consequences of
ADAMTS-15 expression in breast cancer are unknown and are the focus of this
thesis.
ADAMTS-15 reduced the migration of MDA-MB-231 and MCF-7 cells, in a
metalloproteinase-independent manner. This anti-migratory effect likely involves
syndecan-4, since modulation of syndecan-4 expression and signalling
attenuated this effect. In contrast to its effects on cell migration, only wildtype
ADAMTS-15 exhibited an anti-angiogenic effect in in vitro and ex vivo models of
angiogenesis. In experimental metastasis assays, both ADAMTS-15 and E362A
(metalloproteinase inactive form of ADAMTS-15) reduced metastasis of MDAMB-
231 cells to the liver, though paradoxically, ADAMTS-15 but not E362A
enhanced lung colonisation. Taken together these studies demonstrate for the
first time that extracellular ADAMTS-15 has multiple tissue context-dependent
actions on breast tumour pathophysiology, some of which require its proteolytic
activity whereas others do not.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Mia Reeves
Date Deposited: 12 Jun 2014 13:28
Last Modified: 12 Jun 2014 13:28
URI: https://ueaeprints.uea.ac.uk/id/eprint/48756
DOI:

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