Graduation Year

2020

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Mildred Acevedo-Duncan, Ph.D.

Co-Major Professor

Wayne Guida, Ph.D.

Committee Member

David Merkler, Ph.D.

Committee Member

Meera Nanjundan, Ph.D.

Committee Member

Theresa Evans-Nyugen, Ph.D.

Keywords

breast cancer, clear cell ovarian cancer, Ect2, invasion, ovarian cancer, PKC-zeta, Rac1, RhoA

Abstract

Research has demonstrated that the atypical protein kinase C-zeta (PKC-ζ) is a component of many dysregulated pathways in breast and ovarian cancer, including cellular proliferation, survival, and cell cycle upregulation. Breast and ovarian cancers affect women every day and are second and fifth leading cause of cancer death. Women who seek treatments are commonly met with invasive surgeries or chemotherapy. Protein kinase C (PKC) is a family of serine and threonine phosphorylating kinases that have been shown to modulate and transduce signaling cascades that play roles in the development and survival of cancers. Atypical PKC (aPKC), have been heavily suggested to participate in phosphoinositide 3-kinase (PI3K) misregulated cancers (such as breast and ovarian) and inhibition of these pathway branches have demonstrated decreases in malignant behaviors. In our studies, we investigated (1) PKC-ζ protein in breast tissue to evaluate its potential as a biomarker for breast cancer invasion and (2) the effects of the atypical PKC-ζ inhibitor ζ-Stat on ovarian cell lines (TOV21G and ES-2) to determine the outcomes on proliferation and cellular invasion. In breast cancer tissues, we showed that an overexpression of PKC-ζ protein can be indicative of carcinogenesis. We also evaluated the invasive behavior of MDA-MB-231 breast cancer cells upon the knockdown of PKC-ζ with a Transwell invasion assay and an immunofluorescent probe for filamentous actin (F-actin) organization. In ovarian cancer, we utilized clear cell ovarian carcinoma cells (CCOC) because this subtype of ovarian cancer represents 5% of incidence, presents unique pathological features, has poor prognosis and has a high reoccurrence rate after treatment. Overall, our results showed that PKC-ζ is linked to proliferation and invasion in both breast and ovarian cancer. These results illustrate that PKC-ζ plays a role in invasion pathways through the Ras-related C3 botulinum toxin substrate 1 (Rac1) and Ras homolog gene family member A (RhoA). Additionally, our results showed that TOV21G tumor growth in athymic female mice was decreased when treated with the PKC-ζ inhibitor, ζ-Stat. These data suggests that PKC-ζ is a biomarker and a novel target in the carcinogenesis of breast and CCOC and its inhibition by way of ζ-Stat decreased the rate of proliferation, tumor growth and expression of invasive protein pathways.

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