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dc.contributor.advisorLeslie M. Shaw, PhD
dc.contributor.authorMatthew-Onabanjo, Asia N
dc.date2022-08-11T08:08:38.000
dc.date.accessioned2022-08-23T16:02:04Z
dc.date.available2022-08-23T16:02:04Z
dc.date.issued2019-06-27
dc.date.submitted2019-08-06
dc.identifier.doi10.13028/8zqt-8797
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31258
dc.description.abstractBECN1 is a haploinsufficient tumor suppressor gene that is monoallelically deleted or epigenetically silenced in many human cancers. In breast cancer, 40% of tumors exhibit monoallelic deletion of Beclin 1. Additionally, low Beclin 1 mRNA expression is observed in aggressive breast cancer subtypes and reduced expression is an independent predictor of overall patient survival. The role of Beclin 1 in cancer has almost exclusively been attributed to its function in autophagy. However, our lab demonstrated an alternative role for Beclin 1 in the regulation of growth factor receptor signaling that could contribute to cancer. The goal of my thesis project was to investigate the molecular basis by which Beclin 1 regulates breast tumor growth and progression in vivo. Using in vivo models, I discovered that Beclin 1 promotes endosomal recruitment of hepatocyte growth factor tyrosine kinase substrate (HRS), which is necessary for sorting receptors to intraluminal vesicles for signal silencing and degradation. Beclin 1-dependent recruitment of HRS results in the autophagy-independent regulation of endocytic trafficking and degradation of the epidermal growth factor (EGFR) and transferrin (TFR1) receptors. When Beclin 1 expression is low, endosomal HRS recruitment is reduced and receptor function is sustained to drive tumor proliferation. An autophagy-independent role for Beclin 1 in regulating tumor metabolism was also observed. Collectively, my results demonstrate a novel role for Beclin 1 in impeding tumor growth by coordinating the regulation of growth promoting receptors. These data provide an explanation for how low levels of Beclin 1 facilitate tumor proliferation and contribute to poor cancer outcomes, independently of autophagy.
dc.language.isoen_US
dc.rightsLicensed under a Creative Commons license
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBeclin 1
dc.subjectHRS
dc.subjectEndocytosis
dc.subjectTumor Proliferation
dc.subjectBreast Cancer
dc.subjectMetabolism
dc.subjectBiology
dc.subjectCancer Biology
dc.subjectLaboratory and Basic Science Research
dc.subjectNeoplasms
dc.titleNovel Insight into the Autophagy-Independent Functions of Beclin 1 in Tumor Growth
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2047&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/1038
dc.legacy.embargo2021-06-01T00:00:00-07:00
dc.identifier.contextkey15071238
refterms.dateFOA2022-08-25T04:51:06Z
html.description.abstract<p><em>BECN1</em> is a haploinsufficient tumor suppressor gene that is monoallelically deleted or epigenetically silenced in many human cancers. In breast cancer, 40% of tumors exhibit monoallelic deletion of Beclin 1. Additionally, low Beclin 1 mRNA expression is observed in aggressive breast cancer subtypes and reduced expression is an independent predictor of overall patient survival. The role of Beclin 1 in cancer has almost exclusively been attributed to its function in autophagy. However, our lab demonstrated an alternative role for Beclin 1 in the regulation of growth factor receptor signaling that could contribute to cancer. The goal of my thesis project was to investigate the molecular basis by which Beclin 1 regulates breast tumor growth and progression <em>in vivo. </em></p> <p>Using <em>in vivo </em>models, I discovered that Beclin 1 promotes endosomal recruitment of hepatocyte growth factor tyrosine kinase substrate (HRS), which is necessary for sorting receptors to intraluminal vesicles for signal silencing and degradation. Beclin 1-dependent recruitment of HRS results in the autophagy-independent regulation of endocytic trafficking and degradation of the epidermal growth factor (EGFR) and transferrin (TFR1) receptors. When Beclin 1 expression is low, endosomal HRS recruitment is reduced and receptor function is sustained to drive tumor proliferation. An autophagy-independent role for Beclin 1 in regulating tumor metabolism was also observed. Collectively, my results demonstrate a novel role for Beclin 1 in impeding tumor growth by coordinating the regulation of growth promoting receptors. These data provide an explanation for how low levels of Beclin 1 facilitate tumor proliferation and contribute to poor cancer outcomes, independently of autophagy.</p>
dc.identifier.submissionpathgsbs_diss/1038
dc.contributor.departmentMolecular, Cell and Cancer Biology
dc.description.thesisprogramCancer Biology
dc.identifier.orcid0000-0003-4803-5926


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