Characterization of Effects of Muc1 Expression on Epidermal Growth Factor Receptor Signaling in Breast Cancer

Persistent Link:
http://hdl.handle.net/10150/194355
Title:
Characterization of Effects of Muc1 Expression on Epidermal Growth Factor Receptor Signaling in Breast Cancer
Author:
Pochampalli, Mamata Rani
Issue Date:
2006
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:
EGF receptors are key regulators of cell survival and growth in normal and transformed tissues. Ligand binding results in formation of homo/hetero dimers of these receptors, followed by activation of the kinase activity and subsequent tyrosine phosphorylation of many downstream molecules. The activation of these receptors is not only mediated by the binding of their cognate ligands, but by transactivaton by other molecules as well. Recent studies have identified an oncogenic glycoprotein MUC1 as a binding partner for EGFR and that MUC1 expression can potentiate EGFR-dependent signal transduction. After receptor activation, EGFR is typically downregulated via an endocytic pathway that results in receptor degradation or recycling. We report here that MUC1 expression inhibits the degradation of ligand-activated erbB1. In addition, MUC1 expression results in prolonged activation of Akt, but not ERK1,2 MAPKinase. The MUC1-mediated protection against degradation occurs with a decrease in EGF-stimulated ubiquitination of erbB1, and an increase in erbB1 recycling. We then utilized the WAP-TGFα transgenic mouse model of breast cancer and determined that a loss of Muc1 expression dramatically alters mammary tumor progression. While 100% of WAP-TGFα/Muc1^(+/+) mice form mammary gland tumors, only 37% of WAP-TGFα/Muc1^(-/-) form tumors. Furthermore, expression of cyclin D1 expression is significantly suppressed in tumors derived from WAPTGFα/Muc1^(-/-) animals, and loss of Muc1 expression resulted in a significant inhibition in the formation of hyperplastic lesions in the mammary gland. We also observed metastatic pulmonary adenocarcinoma (1/29) and perivascular lymphoma of unknown origin (28/29) in the WAP-TGFα transgenic mice but not in the WAP TGFα/Muc1^(-/-) animals. To determine the effects of Muc1 expression on metastasis in a model lacking perivascular lymphoma, we crossed MMTV-Wnt-1 and MMTV-MUC1 transgenic mice and evaluated interactions between Muc1 and EGFR. Although the MMTV-Wnt-1 mice are non-metastatic, a majority (6/10) of the bitransgenic MMTVWnt- 1/MMTV-MUC1 formed pulmonary metastases. Furthermore, overexpression of MUC1 increases the breast cancer cell invasion in vitro. The MUC1 induced increase in invasion is found to be EGF and EGFR-kinase dependent. Collectively, these data indicate that MUC1 expression contributes to many of the hallmarks of cancer and in addition, is an important modulator of EGFR-associated mammary tumor progression.
Type:
text; Electronic Dissertation
Keywords:
MUC1; EGFR; MOUSE MODELS; HUMAN BREAST CANCER CELL LINES; BREAST CANCER
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Molecular & Cellular Biology; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Schroeder, Joyce A.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleCharacterization of Effects of Muc1 Expression on Epidermal Growth Factor Receptor Signaling in Breast Canceren_US
dc.creatorPochampalli, Mamata Ranien_US
dc.contributor.authorPochampalli, Mamata Ranien_US
dc.date.issued2006en_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.abstractEGF receptors are key regulators of cell survival and growth in normal and transformed tissues. Ligand binding results in formation of homo/hetero dimers of these receptors, followed by activation of the kinase activity and subsequent tyrosine phosphorylation of many downstream molecules. The activation of these receptors is not only mediated by the binding of their cognate ligands, but by transactivaton by other molecules as well. Recent studies have identified an oncogenic glycoprotein MUC1 as a binding partner for EGFR and that MUC1 expression can potentiate EGFR-dependent signal transduction. After receptor activation, EGFR is typically downregulated via an endocytic pathway that results in receptor degradation or recycling. We report here that MUC1 expression inhibits the degradation of ligand-activated erbB1. In addition, MUC1 expression results in prolonged activation of Akt, but not ERK1,2 MAPKinase. The MUC1-mediated protection against degradation occurs with a decrease in EGF-stimulated ubiquitination of erbB1, and an increase in erbB1 recycling. We then utilized the WAP-TGFα transgenic mouse model of breast cancer and determined that a loss of Muc1 expression dramatically alters mammary tumor progression. While 100% of WAP-TGFα/Muc1^(+/+) mice form mammary gland tumors, only 37% of WAP-TGFα/Muc1^(-/-) form tumors. Furthermore, expression of cyclin D1 expression is significantly suppressed in tumors derived from WAPTGFα/Muc1^(-/-) animals, and loss of Muc1 expression resulted in a significant inhibition in the formation of hyperplastic lesions in the mammary gland. We also observed metastatic pulmonary adenocarcinoma (1/29) and perivascular lymphoma of unknown origin (28/29) in the WAP-TGFα transgenic mice but not in the WAP TGFα/Muc1^(-/-) animals. To determine the effects of Muc1 expression on metastasis in a model lacking perivascular lymphoma, we crossed MMTV-Wnt-1 and MMTV-MUC1 transgenic mice and evaluated interactions between Muc1 and EGFR. Although the MMTV-Wnt-1 mice are non-metastatic, a majority (6/10) of the bitransgenic MMTVWnt- 1/MMTV-MUC1 formed pulmonary metastases. Furthermore, overexpression of MUC1 increases the breast cancer cell invasion in vitro. The MUC1 induced increase in invasion is found to be EGF and EGFR-kinase dependent. Collectively, these data indicate that MUC1 expression contributes to many of the hallmarks of cancer and in addition, is an important modulator of EGFR-associated mammary tumor progression.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectMUC1en_US
dc.subjectEGFRen_US
dc.subjectMOUSE MODELSen_US
dc.subjectHUMAN BREAST CANCER CELL LINESen_US
dc.subjectBREAST CANCERen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMolecular & Cellular Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairSchroeder, Joyce A.en_US
dc.contributor.committeememberMartinez, Jesse D.en_US
dc.contributor.committeememberNelson, Mark A.en_US
dc.contributor.committeememberParker, Roy R.en_US
dc.contributor.committeememberBowden, Tim G.en_US
dc.identifier.proquest1875en_US
dc.identifier.oclc659746433en_US
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