Date Available

8-5-2017

Year of Publication

2015

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Behavioral Science

First Advisor

Dr. Kathleen L. O’Connor

Second Advisor

Dr. Thomas Kelly

Abstract

Integrins are cellular adhesion molecules that bind cells to the extracellular matrix. The integrin α6β4, a receptor for laminins, is predominantly expressed on epithelial cells where it is present at the basal surface adjacent to the basement membrane. This integrin plays a critical role in maintaining normal cellular functions, yet has also been implicated in promoting invasion and metastasis in human malignancies. While overexpression of the integrin α6β4 has been detected in select human cancers, the clinical significance of integrin α6β4 expression in a number of malignancies has not been determined. The purpose of this study was to examine integrin α6β4 expression as it relates to clinical variables and patient outcomes in tumors of the lung, breast, and central nervous system. In order to study integrin α6β4 protein expression in patient-derived tumors, tissue microarrays were constructed and sections were stained using immunohistochemistry for the integrin β4 subunit. Integrin β4 mRNA levels in patient-derived tumors were also examined using publicly available gene expression datasets. Integrin β4 expression was found to be elevated in lung squamous cell carcinoma, and its overexpression was associated with venous invasion and decreased overall survival among patients with non-small cell lung cancer. In gliomas, integrin β4 was highly expressed in glioblastomas when compared to lower grade gliomas and non-neoplastic brain tissue. Integrin β4 expression was shown to be an adverse prognostic marker in gliomas, and furthermore, integrin β4 expression was reduced in gliomas with mutations in IDH1. In breast cancer, integrin α6β4 expression was found to be elevated in triple negative tumors, and in one cohort, elevated integrin β4 expression was associated with HER2 overexpression. In summary, I have shown that integrin β4 expression is elevated in a number of aggressive human malignancies, and that its expression associates with poor prognosis in these tumors.

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