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dc.contributor.advisorGuilford, Parry
dc.contributor.authorFrick, James A.
dc.date.available2016-10-25T22:37:50Z
dc.date.copyright2016
dc.identifier.citationFrick, J. A. (2016). Cytoskeletal and mitotic partners for synthetic lethal targeting of E-cadherin-deficient carcinoma (Thesis, Master of Science). University of Otago. Retrieved from http://hdl.handle.net/10523/6865en
dc.identifier.urihttp://hdl.handle.net/10523/6865
dc.description.abstractHereditary diffuse gastric cancer (HDGC) is the familial predisposition to poorly-differentiated, diffuse gastric adenocarcinoma. It is inherited in an autosomal dominant manner and shows high penetrance for diffuse gastric cancer as well as lobular breast cancer. Due to the unreliability of endoscopic detection, the primary management strategy for HDGC is prophylactic total gastrectomy. There is an urgent need for effective drugs for use in conjunction with screening in order to mitigate reliance on surgery. Germline inactivating mutation of the tumour suppressor gene E-cadherin (CDH1) and its functional relatives accounts for the majority of HDGC diagnoses. E-cadherin is a transmembrane protein that plays key roles in establishing and maintaining cell-cell adhesions, apicobasal polarity and mitosis. Although not amenable to conventional drug targeting, the loss of E-cadherin is predicted to create vulnerabilities that can be targeted. Synthetic lethal interactions occur between two genes where only inactivation of both genes is lethal, while inactivation of either gene alone is tolerated. Candidate synthetic lethal targets were silenced with shRNA and drugs in an isogenic (CDH1-/- and CDH1+/+) MCF10A background. Quantitation of gene expression and analysis of cell viability following treatment was used to assess synthetic lethal effect. In this investigation, microtubule-associated targets MAST2 and MAP1B, and mitotic regulators Aurora-A and -B kinase, were identified as vulnerabilities in an E-cadherin-deficient context. Microtubules have been the targets of many drugs since the advent of chemotherapy, and represent a central set of functions that become perturbed in E-cadherin-deficient cells. Given the role of E-cadherin, it is rational to target microtubule and mitotic processes and further investigation of agents that target these functions is warranted.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectcancer
dc.subjecthereditary
dc.subjecttumour
dc.subjectgastric cancer
dc.subjectHDGC
dc.subjectCDH1
dc.subjectdiffuse gastric
dc.subjectmicrotubules
dc.subjectmitosis
dc.subjectsynthetic lethal
dc.subjectsynthetic lethality
dc.subjectMCF10a
dc.subjectlentiviral shRNA
dc.titleCytoskeletal and mitotic partners for synthetic lethal targeting of E-cadherin-deficient carcinoma
dc.typeThesis
dc.date.updated2016-10-25T22:04:36Z
dc.language.rfc3066en
thesis.degree.disciplineBiochemistry
thesis.degree.nameMaster of Science
thesis.degree.grantorUniversity of Otago
thesis.degree.levelMasters
otago.openaccessOpen
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