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dc.contributor.advisorTu, Yapingen_US
dc.contributor.authorKirui, Josephen_US
dc.date.accessioned2011-05-13T19:26:17Z
dc.date.available2011-05-13T19:26:17Z
dc.date.issued2011-05-07en_US
dc.identifier.otherKirui Thesis Final.pdf
dc.identifier.urihttp://hdl.handle.net/10504/16850
dc.description.abstractThe G protein coupled receptors (GPCRs) convey signals mainly via heterotrimeric G proteins in the form of Gα-GTP and Gβγ subunits. Recent studies show that expression of Gβγ-sequestering peptide derived from the carboxyl terminus of β-adrenergic receptor kinase (βARKct), attenuates multiple oncogenic pathways, thus suppressing prostate cancer formation and growth. In addition, an inhibitor of the Gα/Gβγ protein complex has been shown to have anti-tumor activity. Thus Gβγ subunits may function as potential links between GPCRs and tumor transformation and growth. The aim of the present study was to determine whether blockade of Gβ signaling pathways suppresses breast cancer cell migration and invasion, critical components of cancer metastasis. Conditioned media (CM) of NIH-3T3 fibroblasts contains chemoattractants that activate different GPCRs. Expression of βARKct attenuated NIH-3T3 CM-induced migration and invasion of both metastatic breast cancer MDA-MB-231 and MDAMB-436 cells by 40-50%. Migration and invasion of those cells in response to NIH-3T3 CM were also blocked by M119K, an inhibitor of Gβ , with maximum inhibition exceeding 80% and IC50 values of 1-2 μM. Activation of Gi-protein coupled CXC chemokine receptor 4 (CXCR4) promotes breast cancer metastasis. M119K suppressed CXCR4-dependent MDA-MB-231 cell migration by 75% with an IC50 value of 0.9 ± 0.2 μM. Furthermore, 10 μM M119K attenuated CXCR4-stimulated, Rac-dependent formation of lamellipodia, a key structure required for cell migration and invasion. In contrast, CXCR4-dependent inhibition of adenylyl cyclase, a Giα-mediated response in MDA-MB-231 cells, was not blocked by M119K but was blocked by pertussis toxin, which selectively inactivates Giα. In addition, a M119K analogue, gallein, suppressed anchorage-indpendent growth of metastatic breast cancer cells. Our study demonstrates critical roles of Gβ signaling pathways in breast cancer cell migration, invasion and clonogenicity thus serves as a potential utility for effective treatment of invasive breast cancer.en_US
dc.language.isoen_USen_US
dc.publisherCreighton Universityen_US
dc.rightsCopyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.en_US
dc.subject.meshCarcinoma, Ductal--geneticsen_US
dc.subject.meshBreast Neoplasms--geneticsen_US
dc.subject.meshGTP-Binding Protein beta Subunits--metabolismen_US
dc.subject.meshGTP-Binding Protein gamma Subunits--metabolismen_US
dc.titleMolecular Study of Gβγ Dependent Breast Cancer Cell Migration and Invasionen_US
dc.typeThesis
dc.rights.holderJoseph Kiruien_US
dc.publisher.locationOmaha, Nebraskaen_US
dc.description.noteProQuest Traditional Publishing Optionen_US
dc.description.pagesx, 31 pagesen_US
dc.contributor.cuauthorKirui, Josephen_US
dc.degree.levelMS (Master of Science)en_US
dc.degree.disciplinePharmacology (graduate program)en_US
dc.degree.nameM.S. in Pharmacologyen_US
dc.degree.grantorGraduate Schoolen_US
dc.degree.committeeAbel, Peteren_US
dc.degree.committeeScofield, Margaret A.en_US
dc.degree.committeeMurray, Thomas F.en_US
dc.degree.committeeHansen, Laura A.en_US


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