Title

Dissecting the Role of Protein Kinase C-Epsilon in Breast Cancer

Date of Award

12-1-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Graduate School of Biomedical Sciences

First Advisor

Alakananda Basu

Abstract

Protein kinase C-epsilon (PKCε) has pro-tumor functions in many cancers including breast cancer. The purpose of this dissertation is to understand the role of PKCε in fundamental processes that are associated with breast cancer development and progression.

PKCε is known to promote the survival of breast cancer cells. Autophagy is a process of cellular self-digestion that can mediate cell survival during stress. We have found that PKCε overexpression increases the basal autophagy in breast cancer cells while its depletion reduces it. Moreover, the effect of PKCε on autophagy is isozyme specific. Regulation by PKCε is not limited to basal autophagy as it also mediated starvation-induced autophagy. Looking for the possible mechanisms, we found that PKCε negatively regulates mammalian target of rapamycin (mTOR), which is the master regulator of autophagy. These results show that PKCε positively regulates autophagy, likely, via inhibition of mTOR.

PKCε overexpression in mammary epithelial cells led to morphological changes indicating its role in regulation of cell plasticity. Further analysis revealed that PKCε promotes epithelial to mesenchymal transition (EMT), which is an early step in cancer metastasis. In addition, PKCε mediated transforming growth factor-beta (TGFβ)-induced EMT partially via Snail, which is a crucial EMT effector. Moreover, PKCε promoted cell migration and anoikis Ii resistance which are hallmarks of EMT. To examine the phenotypic effect of PKCε manipulation in a physiologically relevant context, we employed three dimensional (3D) cell culture model. We found that PKCε overexpression led to disruption of acinar morphogenesis in 3D culture. These results indicate a causal role for PKCε in breast tumor development and progression

Comments

Kirti Jain, Dissecting the role of protein kinase C-epsilon in breast cancer. Doctor of Philosophy (Biochemistry and Molecular Biology) November 2013, pp 154, 24 illustrations, 197 references Available online December 2015

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