Graduation Date

Spring 5-5-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Dr. Jennifer Black

Abstract

Protein kinase Cα (PKCα) is a member of the PKC family of serine/threonine kinases that regulate many fundamental cellular processes, including cell proliferation, differentiation, survival and transformation. The impact of PKCα on tumorigenesis, and whether it acts as an oncogene or tumor suppressor, has been debated over the years. The overall goal of this study was to establish the functional role of PKCα in endometrial carcinogenesis. Results from this study broaden our knowledge of PKCα signaling and add to our understanding of its role in tumor development.

As understanding of the role of PKCα signaling in the uterus is limited, we first examined the expression and activation of PKCα in the normal endometrium. Our analysis revealed cyclical activation of PKCα, linked to hormonal fluctuations and negatively correlated with epithelial proliferation, suggesting that PKCα is a growth inhibitory kinase in the endometrium.

Historically, PKC isozymes have been recognized as oncoproteins as they are activated by the tumor promoting phorbol esters. However, accumulating evidence indicates that PKCs can be inhibitory in some cancers, with recent findings propelling a shift in focus to understanding tumor suppressive functions of these enzymes. Here, we report that PKCα acts as a tumor suppressor in PI3K/AKT-driven endometrial cancer. PKCα deficiency, due to transcriptional repression, is associated with aggressive disease and poor prognosis in endometrial cancer patients. Activation of PKCα induces PP2A activity, leading to hypophosphorylation of AKT and potently inhibiting the growth of endometrial cancer cells under anchorage-independent conditions. In murine models, PKCα loss is a rate-limiting event for initiation of endometrial tumorigenesis, as demonstrated by increased tumor burden in mice lacking PKCα.

More than 90% of endometrial cancer cases are characterized by AKT hyperactivation as the result of mutations in multiple PI3K/AKT pathway components, including PTEN, PIK3CA, PIK3R1, and AKT. Mutations in these molecules often coexist in EC, indicating that EC development requires full, unopposed activation of PI3K/AKT signaling. Results from our study show that PKCα is a negative regulator of AKT activation in the endometrium, which can override hyperactivation of the PI3K/AKT pathway in endometrial cancer cells. Loss of this kinase in the context of other molecular aberrations, such as mutations in PTEN or PI3K, leads to further hyperactivation of AKT, enhancing tumor cell growth. Together, our data point to PKCα as a crucial tumor suppressor in the endometrium, with deregulation of a PKCα→PP2A signaling axis leading to robust AKT activation and enhanced endometrial tumorigenesis.

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