MUC1 Affects EGFR Trafficking and Signaling in Breast Cancer Cells

Persistent Link:
http://hdl.handle.net/10150/195711
Title:
MUC1 Affects EGFR Trafficking and Signaling in Breast Cancer Cells
Author:
El Bejjani, Rachid Michel
Issue Date:
2008
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:
MUC1 is a large transmembrane glycoprotein that is overexpressed in about 90% of breast cancers. Importantly, MUC1 overexpression is not a mere consequence of breast tumorigenesis but can sufficiently induce breast cancer formation when overexpressed in the mammary gland. The oncogenic mechanism of MUC1 overexpression remains largely unknown. However, recent studies point towards an important role for MUC1 in signaling downstream of the epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, and a key mediator of tumorigenesis. Trafficking represents a critical aspect of MUC1 and EGFR biology, and both are endocytosed via a clathrin dependent pathway but follow different trafficking routes. While MUC1 is constitutively internalized and recycled back to the plasma membrane, EGFR is internalized in response to ligand binding and is ultimately trafficked to the lysosome to be degraded. EGFR degradation terminates its downstream signaling which when overactive can lead to cancer progression.In this work, we have demonstrated an important role for MUC1 in regulating EGFR trafficking. We showed that MUC1 expression can enhance the internalization of EGFR while inhibiting its ubiquitination. This results in a decrease in the degradation of the receptor and in an increased recycling in response to EGF. We then investigated the mechanism behind MUC1-dependent EGFR trafficking. We showed that, when MUC1 is present, EGFR colocalizes with MUC1 at the Rab11 and RME-1 positive perinuclear endocytic recycling compartment (ERC). Interestingly, MUC1 expression did not significantly alter the localization of EGFR at the Rab5-positive early endosome; However, MUC1 knockdown restored EGFR trafficking towards Rab7-positive late endosomes and away from the perinuclear ERC. These results describe a novel MUC1-dependent EGFR trafficking pathway in breast cancer cells. We investigated the effect of MUC1-dependent EGFR trafficking on EGFR signaling in cancer by analyzing tumor lysates from a Wnt-1 mouse model of breast cancer (MMTV-Wnt-1) crossed into a MUC1 overexpressing (MMFW) or a MUC1 null (WK) background. We observed an enhanced activation of ErbB1 and 2 but not ErbB3 in these tumors. This was accompanied by an increase in AKT but not MAPK pathway activation and in an increase in β-catenin and cyclinD1 expression. Taken together, our results identify MUC1 as a modulator of EGFR trafficking and describe a novel MUC1-dependent EGFR trafficking pathway. This altered EGFR trafficking results in enhanced EGFR activation and in the preferential activation of the PI3K/AKT pathway which could have significant implications for breast cancer biology and therapy.
Type:
text; Electronic Dissertation
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Molecular & Cellular Biology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Joyce, Schdoeder A.
Committee Chair:
Joyce, Schdoeder A.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleMUC1 Affects EGFR Trafficking and Signaling in Breast Cancer Cellsen_US
dc.creatorEl Bejjani, Rachid Michelen_US
dc.contributor.authorEl Bejjani, Rachid Michelen_US
dc.date.issued2008en_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.abstractMUC1 is a large transmembrane glycoprotein that is overexpressed in about 90% of breast cancers. Importantly, MUC1 overexpression is not a mere consequence of breast tumorigenesis but can sufficiently induce breast cancer formation when overexpressed in the mammary gland. The oncogenic mechanism of MUC1 overexpression remains largely unknown. However, recent studies point towards an important role for MUC1 in signaling downstream of the epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, and a key mediator of tumorigenesis. Trafficking represents a critical aspect of MUC1 and EGFR biology, and both are endocytosed via a clathrin dependent pathway but follow different trafficking routes. While MUC1 is constitutively internalized and recycled back to the plasma membrane, EGFR is internalized in response to ligand binding and is ultimately trafficked to the lysosome to be degraded. EGFR degradation terminates its downstream signaling which when overactive can lead to cancer progression.In this work, we have demonstrated an important role for MUC1 in regulating EGFR trafficking. We showed that MUC1 expression can enhance the internalization of EGFR while inhibiting its ubiquitination. This results in a decrease in the degradation of the receptor and in an increased recycling in response to EGF. We then investigated the mechanism behind MUC1-dependent EGFR trafficking. We showed that, when MUC1 is present, EGFR colocalizes with MUC1 at the Rab11 and RME-1 positive perinuclear endocytic recycling compartment (ERC). Interestingly, MUC1 expression did not significantly alter the localization of EGFR at the Rab5-positive early endosome; However, MUC1 knockdown restored EGFR trafficking towards Rab7-positive late endosomes and away from the perinuclear ERC. These results describe a novel MUC1-dependent EGFR trafficking pathway in breast cancer cells. We investigated the effect of MUC1-dependent EGFR trafficking on EGFR signaling in cancer by analyzing tumor lysates from a Wnt-1 mouse model of breast cancer (MMTV-Wnt-1) crossed into a MUC1 overexpressing (MMFW) or a MUC1 null (WK) background. We observed an enhanced activation of ErbB1 and 2 but not ErbB3 in these tumors. This was accompanied by an increase in AKT but not MAPK pathway activation and in an increase in β-catenin and cyclinD1 expression. Taken together, our results identify MUC1 as a modulator of EGFR trafficking and describe a novel MUC1-dependent EGFR trafficking pathway. This altered EGFR trafficking results in enhanced EGFR activation and in the preferential activation of the PI3K/AKT pathway which could have significant implications for breast cancer biology and therapy.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMolecular & Cellular Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorJoyce, Schdoeder A.en_US
dc.contributor.chairJoyce, Schdoeder A.en_US
dc.contributor.committeememberLance, Peteren_US
dc.contributor.committeememberFares, Hannaen_US
dc.contributor.committeememberFrans, Taxen_US
dc.contributor.committeememberEmmanuelle, Meuilleten_US
dc.identifier.proquest10004en_US
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