DETERMINING THE ROLE OF MUC1 AND BETA-CATENIN ON THE EPIDERMAL GROWTH FACTOR RECEPTOR SIGNALING AND LOCALIZATION IN BREAST CANCER

Persistent Link:
http://hdl.handle.net/10150/194738
Title:
DETERMINING THE ROLE OF MUC1 AND BETA-CATENIN ON THE EPIDERMAL GROWTH FACTOR RECEPTOR SIGNALING AND LOCALIZATION IN BREAST CANCER
Author:
Bitler, Benjamin Guy
Issue Date:
2010
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
The epidermal growth factor family of receptors is important in the development and progression of many types of cancers including, breast, lung, and glioblastoma. The family consists of 4 members (EGFR/erbB1, Her2/erbB2, erbB3, and erbB4). In all breast cancer cases, EGFR expression is deregulated 20 to 30% of the time; however in the most aggressive form of breast cancer (basal-like) EGFR expression is upregulated in 60% of cases. EGFR's expression and activity can be altered in transformed cells through a variety of mechanisms, such as novel protein-protein interactions, gene amplification, mutations, and loss of regulatory proteins. In this work we have examined the role of cancer specific protein interactions of EGFR with MUC1 and beta-catenin in the progression of breast cancer.Herein I report that the interaction of MUC1 and EGFR in breast cancer cells alters EGFR localization by promoting EGFR nuclear translocation. Importantly, I discovered that the presence of MUC1 mediates EGFR's interaction with chromatin. More specifically, I found that EGFR interacts with the cyclin D1 promoter region in a MUC1-dependent fashion which resulted in a significant increase in cyclin D1 protein expression. Nuclear EGFR localization has been shown to correlate with resistance to anti-EGFR therapies, which indicates that MUC1's interaction with EGFR could be a mechanism of resistance.MUC1's interaction with both EGFR and beta-catenin can promote transformation therefore a peptide therapy was developed, PMIP, which mimics the hypothesized interaction domains of MUC1's cytoplasmic tail. PMIP was designed to inhibit the interaction of MUC1/EGFR and MUC1/beta-catenin thereby regulating EGFR expression and promoting beta-catenin localization to adherens junctions. PMIP effectively enters the cytosol of cells and inhibits the target interactions. Importantly, PMIP inhibited invasion and proliferation of breast cancer cells and in mice significantly reduced the growth rate of breast cancer xenograft and genetically-driven tumors. This study demonstrated that the use of peptides to inhibit intracellular protein interactions is a viable option that would have limited toxic side-effects. Overall, this work reveals a new regulatory role of EGFR localization and activity by MUC1 and that this mechanism is viable therapeutic breast cancer target.Lastly, in a mouse model of breast cancer I examined the role of EGFR tyrosine kinase activity in beta-catenin dependent tumorigenesis. A transgenic mouse model of breast cancer, MMTV-Wnt-1, was bred onto an EGFR kinase deficient background. I discovered that the loss of EGFR kinase activity in this model resulted in a significant delay in tumor onset and inhibited tumor growth. These findings indicate a cooperation of EGFR and beta-catenin dependent signaling pathways, which promote transformation of glandular epithelial cells.
Type:
text; Electronic Dissertation
Keywords:
beta-catenin; breast cancer; EGFR; MUC1; Nuclear Localization; Trafficking
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Cancer Biology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Schroeder, Joyce A.
Committee Chair:
Schroeder, Joyce A.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleDETERMINING THE ROLE OF MUC1 AND BETA-CATENIN ON THE EPIDERMAL GROWTH FACTOR RECEPTOR SIGNALING AND LOCALIZATION IN BREAST CANCERen_US
dc.creatorBitler, Benjamin Guyen_US
dc.contributor.authorBitler, Benjamin Guyen_US
dc.date.issued2010en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThe epidermal growth factor family of receptors is important in the development and progression of many types of cancers including, breast, lung, and glioblastoma. The family consists of 4 members (EGFR/erbB1, Her2/erbB2, erbB3, and erbB4). In all breast cancer cases, EGFR expression is deregulated 20 to 30% of the time; however in the most aggressive form of breast cancer (basal-like) EGFR expression is upregulated in 60% of cases. EGFR's expression and activity can be altered in transformed cells through a variety of mechanisms, such as novel protein-protein interactions, gene amplification, mutations, and loss of regulatory proteins. In this work we have examined the role of cancer specific protein interactions of EGFR with MUC1 and beta-catenin in the progression of breast cancer.Herein I report that the interaction of MUC1 and EGFR in breast cancer cells alters EGFR localization by promoting EGFR nuclear translocation. Importantly, I discovered that the presence of MUC1 mediates EGFR's interaction with chromatin. More specifically, I found that EGFR interacts with the cyclin D1 promoter region in a MUC1-dependent fashion which resulted in a significant increase in cyclin D1 protein expression. Nuclear EGFR localization has been shown to correlate with resistance to anti-EGFR therapies, which indicates that MUC1's interaction with EGFR could be a mechanism of resistance.MUC1's interaction with both EGFR and beta-catenin can promote transformation therefore a peptide therapy was developed, PMIP, which mimics the hypothesized interaction domains of MUC1's cytoplasmic tail. PMIP was designed to inhibit the interaction of MUC1/EGFR and MUC1/beta-catenin thereby regulating EGFR expression and promoting beta-catenin localization to adherens junctions. PMIP effectively enters the cytosol of cells and inhibits the target interactions. Importantly, PMIP inhibited invasion and proliferation of breast cancer cells and in mice significantly reduced the growth rate of breast cancer xenograft and genetically-driven tumors. This study demonstrated that the use of peptides to inhibit intracellular protein interactions is a viable option that would have limited toxic side-effects. Overall, this work reveals a new regulatory role of EGFR localization and activity by MUC1 and that this mechanism is viable therapeutic breast cancer target.Lastly, in a mouse model of breast cancer I examined the role of EGFR tyrosine kinase activity in beta-catenin dependent tumorigenesis. A transgenic mouse model of breast cancer, MMTV-Wnt-1, was bred onto an EGFR kinase deficient background. I discovered that the loss of EGFR kinase activity in this model resulted in a significant delay in tumor onset and inhibited tumor growth. These findings indicate a cooperation of EGFR and beta-catenin dependent signaling pathways, which promote transformation of glandular epithelial cells.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectbeta-cateninen_US
dc.subjectbreast canceren_US
dc.subjectEGFRen_US
dc.subjectMUC1en_US
dc.subjectNuclear Localizationen_US
dc.subjectTraffickingen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorSchroeder, Joyce A.en_US
dc.contributor.chairSchroeder, Joyce A.en_US
dc.contributor.committeememberHeimark, Ronalden_US
dc.contributor.committeememberMartinez, Jesseen_US
dc.contributor.committeememberNagle, Raymonden_US
dc.contributor.committeememberGerner, Eugeneen_US
dc.identifier.proquest11057en_US
dc.identifier.oclc659754997en_US
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