{"id":{"repo_id":"the-open-u","oai_identifier":"oai:oro.open.ac.uk:52880"},"canonical_url":"https://search.dev.ndltd.org/etd/the-open-u/oai:oro.open.ac.uk:52880","repository":{"repo_id":"the-open-u","name":"The Open University","base_url":"https://oro.open.ac.uk/cgi/oai2"},"display":{"title":"Investigating the Role of the Inhibitor of Apoptosis Proteins (IAPs) in Metastasis Formation","abstract":"Inhibitor of apoptosis proteins (IAPs) constitute a conserved family of molecules, which regulate both apoptosis and receptor signalling. They are often deregulated in cancer cells and represent potential targets for therapy. In my work, I investigated the effect of IAP inhibition <i>in vivo</i> to identify novel down-stream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple negative breast cancer (TNBC) cell line MDA-MB231 were treated with SM83, a Smac mimetic developed in our laboratory that acts as a pan-IAP inhibitor, and tumour nodules were profiled for gene expression. The analysis revealed that the inhibition of IAPs significantly reduces the expression of SNAI2, a zinc finger transcriptional repressor often associated with cancer aggressiveness, resistance to therapy and metastatic potential, especially in breast cancer. By testing several TNBC cell lines, I found that SNAI2 levels is promoted specifically by cellular IAP1 (cIAP1), and not by other IAPs, and that SM83-dependent down-regulation of SNAI2 reduces cancer cell motility. Accordingly, cIAP1 depletion blocks epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway causing the reduction of SNAI2 transcription levels. The inhibition of EGFR signalling stems from the block of receptor signalling and from the down-regulation of its levels, but paradoxically the silencing of cIAP1 promotes EGFR stability rather than its degradation. Nonetheless, EGFR levels decrease upon cIAP1 silencing due to reduced NF-kB-dependent gene expression supporting the notion that cIAP1 controls EGFR in an opposite fashion, promoting its gene expression while causing its degradation. In conclusion, my work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its down-stream mediators. This approach could be particularly effective in tumours characterized by high levels of EGFR and SNAI2, such as TNBCs.","abstract_html":"Inhibitor of apoptosis proteins (IAPs) constitute a conserved family of molecules, which regulate both apoptosis and receptor signalling. They are often deregulated in cancer cells and represent potential targets for therapy. In my work, I investigated the effect of IAP inhibition &lt;i&gt;in vivo&lt;/i&gt; to identify novel down-stream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple negative breast cancer (TNBC) cell line MDA-MB231 were treated with SM83, a Smac mimetic developed in our laboratory that acts as a pan-IAP inhibitor, and tumour nodules were profiled for gene expression. The analysis revealed that the inhibition of IAPs significantly reduces the expression of SNAI2, a zinc finger transcriptional repressor often associated with cancer aggressiveness, resistance to therapy and metastatic potential, especially in breast cancer. By testing several TNBC cell lines, I found that SNAI2 levels is promoted specifically by cellular IAP1 (cIAP1), and not by other IAPs, and that SM83-dependent down-regulation of SNAI2 reduces cancer cell motility. Accordingly, cIAP1 depletion blocks epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway causing the reduction of SNAI2 transcription levels. The inhibition of EGFR signalling stems from the block of receptor signalling and from the down-regulation of its levels, but paradoxically the silencing of cIAP1 promotes EGFR stability rather than its degradation. Nonetheless, EGFR levels decrease upon cIAP1 silencing due to reduced NF-kB-dependent gene expression supporting the notion that cIAP1 controls EGFR in an opposite fashion, promoting its gene expression while causing its degradation. In conclusion, my work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its down-stream mediators. This approach could be particularly effective in tumours characterized by high levels of EGFR and SNAI2, such as TNBCs.","abstract_has_math":false,"creators":["Majorini, Maria Teresa"],"institution":"The Open University","degree_name":"phd","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-01","date_published":"2018-01","updated_at":"2026-07-24T05:02:39Z","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":["Majorini, Maria Teresa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018-01-10"]},{"key":"dc:date.issued","label":"Date","values":["2018-01"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["ARRAY(0x7ffb743952c0)"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["The Open University"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://oro.open.ac.uk/52880/"]},{"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://oro.open.ac.uk/52880/1/PhD%20Thesis%20MAJORINI_D1934968.pdf","https://oro.open.ac.uk/52880/7/GRADPROG%20memo-%20ARC.docx","https://oro.open.ac.uk/52880/8/Library%20deposition%20memo%20%282%29.doc","https://oro.open.ac.uk/52880/9/abstract.pdf","https://oro.open.ac.uk/52880/10/library%20form.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Inhibitor of apoptosis proteins (IAPs) constitute a conserved family of molecules, which regulate both apoptosis and receptor signalling. They are often deregulated in cancer cells and represent potential targets for therapy. In my work, I investigated the effect of IAP inhibition <i>in vivo</i> to identify novel down-stream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple negative breast cancer (TNBC) cell line MDA-MB231 were treated with SM83, a Smac mimetic developed in our laboratory that acts as a pan-IAP inhibitor, and tumour nodules were profiled for gene expression. The analysis revealed that the inhibition of IAPs significantly reduces the expression of SNAI2, a zinc finger transcriptional repressor often associated with cancer aggressiveness, resistance to therapy and metastatic potential, especially in breast cancer. By testing several TNBC cell lines, I found that SNAI2 levels is promoted specifically by cellular IAP1 (cIAP1), and not by other IAPs, and that SM83-dependent down-regulation of SNAI2 reduces cancer cell motility. Accordingly, cIAP1 depletion blocks epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway causing the reduction of SNAI2 transcription levels. The inhibition of EGFR signalling stems from the block of receptor signalling and from the down-regulation of its levels, but paradoxically the silencing of cIAP1 promotes EGFR stability rather than its degradation. Nonetheless, EGFR levels decrease upon cIAP1 silencing due to reduced NF-kB-dependent gene expression supporting the notion that cIAP1 controls EGFR in an opposite fashion, promoting its gene expression while causing its degradation. In conclusion, my work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its down-stream mediators. This approach could be particularly effective in tumours characterized by high levels of EGFR and SNAI2, such as TNBCs."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf","application/vnd.openxmlformats-officedocument.wordprocessingml.document","application/msword"]},{"key":"dc:title","label":"Title","values":["Investigating the Role of the Inhibitor of Apoptosis Proteins (IAPs) in Metastasis Formation"]}]}],"canonical_facts":{"dc:creator":["Majorini, Maria Teresa"],"dc:date":["2018-01-10"],"dc:date.issued":["2018-01"],"dc:description.abstract":["Inhibitor of apoptosis proteins (IAPs) constitute a conserved family of molecules, which regulate both apoptosis and receptor signalling. They are often deregulated in cancer cells and represent potential targets for therapy. In my work, I investigated the effect of IAP inhibition <i>in vivo</i> to identify novel down-stream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple negative breast cancer (TNBC) cell line MDA-MB231 were treated with SM83, a Smac mimetic developed in our laboratory that acts as a pan-IAP inhibitor, and tumour nodules were profiled for gene expression. The analysis revealed that the inhibition of IAPs significantly reduces the expression of SNAI2, a zinc finger transcriptional repressor often associated with cancer aggressiveness, resistance to therapy and metastatic potential, especially in breast cancer. By testing several TNBC cell lines, I found that SNAI2 levels is promoted specifically by cellular IAP1 (cIAP1), and not by other IAPs, and that SM83-dependent down-regulation of SNAI2 reduces cancer cell motility. Accordingly, cIAP1 depletion blocks epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway causing the reduction of SNAI2 transcription levels. The inhibition of EGFR signalling stems from the block of receptor signalling and from the down-regulation of its levels, but paradoxically the silencing of cIAP1 promotes EGFR stability rather than its degradation. Nonetheless, EGFR levels decrease upon cIAP1 silencing due to reduced NF-kB-dependent gene expression supporting the notion that cIAP1 controls EGFR in an opposite fashion, promoting its gene expression while causing its degradation. In conclusion, my work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its down-stream mediators. This approach could be particularly effective in tumours characterized by high levels of EGFR and SNAI2, such as TNBCs."],"dc:format":["application/pdf","application/vnd.openxmlformats-officedocument.wordprocessingml.document","application/msword"],"dc:identifier.uri":["https://oro.open.ac.uk/52880/1/PhD%20Thesis%20MAJORINI_D1934968.pdf","https://oro.open.ac.uk/52880/7/GRADPROG%20memo-%20ARC.docx","https://oro.open.ac.uk/52880/8/Library%20deposition%20memo%20%282%29.doc","https://oro.open.ac.uk/52880/9/abstract.pdf","https://oro.open.ac.uk/52880/10/library%20form.pdf"],"dc:language":["en"],"dc:publisher.department":["ARRAY(0x7ffb743952c0)"],"dc:publisher.institution":["The Open University"],"dc:relation.isreferencedby":["https://oro.open.ac.uk/52880/"],"dc:title":["Investigating the Role of the Inhibitor of Apoptosis Proteins (IAPs) in Metastasis Formation"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["phd"]},"updated_at":"2026-07-24T05:02:39Z"}