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Dissertation
Functional role of integrin alpha5 in ErbB2-mediated oncogenesis of human mammary epithelial cells
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2010
DOI:
https://doi.org/10.17918/00000838
Abstract
The receptor tyrosine kinase ErbB2 is highly expressed in many epithelial tumors. ErbB2 overexpression is associated with disruption of normal mammary tissue architecture, resulting in ductal carcinoma in situ lesions, characterized by ducts filled with cells, in vivo. One mechanism through which oncogenes may promote ductal filling is by allowing cell survival in the absence of adhesion to extracellular matrix. In three dimensional culture models, ErbB2 overexpression leads to anoikis resistance that contributes to luminal filling of mammary epithelial acinar structures. Integrins are key components in cell-matrix signaling that have been shown to affect the activity of some growth factor receptors. Since integrin and growth factor receptors are highly interdependent for proper function, we examined what role, if any, integrin subunits play in ErbB2-mediated anoikis resistance. Using the normal human mammary epithelial cell line, MCF-10A, we have found that the integrin [alpha]5 subunit is a critical player in ErbB2-mediated oncogenesis. Integrin [alpha]5 is specifically upregulated during anoikis and three-dimensional morphogenesis and, more importantly, MCF-10A cells overexpressing ErbB2 upregulate integrin [alpha]5 via the MAP-kinase pathway in both monolayer culture and three-dimensional acinar structures. We also determined that elevated integrin [alpha]5 levels are associated with ErbB2 status in human breast cancer. Moreover, integrin [alpha]5 is required for ErbB2-mediated anoikis resistance and for optimal ErbB2 signaling to the Mek-Erk-Bim axis, as depletion of integrin [alpha]5 reverses anoikis resistance and Bim inhibition. Integrin [alpha]5 is required for full activation of ErbB2 tyrosine phosphorylation activity on Tyr-877, which is important as we provide evidence that ErbB2 phosphorylation is associated with increased c-Src activity in the absence of adhesion. Indeed, inhibition of elevated c-Src activity during cell detachment reverses ErbB2-mediated survival and Bim repression. Thus, under states of low adhesion, integrin [alpha]5 serves as a key mediator of c-Src and ErbB2-survival signaling that is necessary to block expression of the pro-anoikis mediator Bim. These results suggest tyrosine kinase receptors are still dependent on adhesion receptors for optimal signaling even in the absence of adhesion. Taken together, targeting of integrin [alpha]5 represents a potential novel therapeutic approach to ErbB2-positive tumors to reverse anoikis resistance.
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Details
- Title
- Functional role of integrin alpha5 in ErbB2-mediated oncogenesis of human mammary epithelial cells
- Creators
- Keneshia Kellian Haenssen
- Contributors
- Mauricio Reginato (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xviii, 171 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014970184904721