Theses Doctoral

Examining the Role and Regulation of Cell-Cell Adhesion in Aggressive Prostate Cancer

Barber, Alison G.

Prostate cancer is the second leading cause of cancer death in American men, yet despite the prevalence of this disease, there is a distinct lack of prognostic biomarkers for estimating the likelihood of prostate cancer aggressiveness. The loss of cell-cell adhesion is frequently associated with the progression of prostate cancer to a metastatic state. While both adherens junctions and desmosomes are involved in establishing and maintaining this adhesion, previous studies of cell-cell adhesion in prostate cancer have focused solely on the role of adherens junctions, leaving the role of desmosomal adhesion unexplored. The goals of this thesis were to perform a functional analysis of the role and regulation of adherens junctions and desmosomes in aggressive prostate cancer, and to examine the efficacy of classical and desmosomal cadherins as prognostic biomarkers of aggressive prostate cancer. I began this study by characterizing the expression profile of desmosomal cadherins in normal human prostate and metastatic prostate cancer cell lines. This study revealed that DSG2, DSC2, and DSG4 were consistently expressed at a high level in the luminal cells of the prostate. Further, analysis of metastatic prostate cancer cell lines showed that the expression of DSG2 is present in most cell lines examined, while the expression of DSG4 is absent. Following this characterization, I examined the role of E-cadherin and DSG2 in metastatic prostate cancer cell lines. Interestingly, the loss of E-cadherin resulted in the inhibition of extensive primary and metastatic tumor formation, suggesting that E-cadherin may have a role in promoting the progression of prostate cancer in addition to its well-established role as a tumor suppressor. Additionally, the loss of E-cadherin based adherens junctions was not associated with the reciprocal loss of DSG2 based desmosomes, challenging the common belief that the formation of adherens junctions is a prerequisite for the formation of desmosomes. I then examined the regulatory effects of PI3K/AKT signaling on E-cadherin and DSG2 expression in metastatic prostate cancer cell lines. The expression of activated AKT was found to be associated with the inhibition of E-cadherin expression, while the expression of DSG2 was relatively unperturbed in the presence of activated AKT expression. These results suggest that aberrantly activated PI3K/AKT signaling in prostate cancer may result in the loss of E-cadherin expression, and that the loss of E-cadherin and DSG2 expression in prostate cancer may be regulated by separate pathways. Finally, I examined the expression of E-cadherin and DSG2 in a large cohort of patients with prostate cancer to determine whether these cadherins were associated with prostate cancer aggressiveness. Interestingly, the loss of these cadherins was found to be significantly associated with biochemical recurrence demonstrating their potential utility as prognostic markers of aggressive prostate cancer.



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More About This Work

Academic Units
Genetics and Development
Thesis Advisors
Cordon-Cardo, Carlos
Ph.D., Columbia University
Published Here
April 29, 2011