{"id":{"repo_id":"east-anglia","oai_identifier":"oai:ueaeprints.uea.ac.uk:47914"},"canonical_url":"https://search.dev.ndltd.org/etd/east-anglia/oai:ueaeprints.uea.ac.uk:47914","repository":{"repo_id":"east-anglia","name":"University of East Anglia","base_url":"https://ueaeprints.uea.ac.uk/cgi/oai2"},"display":{"title":"Investigation of the functions of Matrix Metalloproteinase-8 (MMP-8) in Mammary Carcinoma Cells","abstract":"Abstract 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. 3 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.","abstract_html":"Abstract 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. 3 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.","abstract_has_math":false,"creators":["Thirkettle, Sally"],"institution":"University of East Anglia","degree_name":"phd","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-04","date_published":"2013-04","updated_at":"2026-07-24T02:11:56Z","subjects":[],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Thirkettle, Sally"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2013-04"]},{"key":"dc:date.issued","label":"Date","values":["2013-04"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["School of Biological Sciences"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of East Anglia"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://ueaeprints.uea.ac.uk/id/eprint/47914/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["phd"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://ueaeprints.uea.ac.uk/id/eprint/47914/1/2013ThirkettleSPhD.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Abstract 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. 3 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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Investigation of the functions of Matrix Metalloproteinase-8 (MMP-8) in Mammary Carcinoma Cells"]}]}],"canonical_facts":{"dc:creator":["Thirkettle, Sally"],"dc:date":["2013-04"],"dc:date.issued":["2013-04"],"dc:description.abstract":["Abstract 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. 3 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."],"dc:format":["application/pdf"],"dc:identifier.uri":["https://ueaeprints.uea.ac.uk/id/eprint/47914/1/2013ThirkettleSPhD.pdf"],"dc:language":["en"],"dc:publisher.department":["School of Biological Sciences"],"dc:publisher.institution":["University of East Anglia"],"dc:relation.isreferencedby":["https://ueaeprints.uea.ac.uk/id/eprint/47914/"],"dc:title":["Investigation of the functions of Matrix Metalloproteinase-8 (MMP-8) in Mammary Carcinoma Cells"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["phd"]},"updated_at":"2026-07-24T02:11:56Z"}