Author ORCID Identifier

0000-0002-4644-3080

Date of Graduation

8-2017

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dr.Sendurai Mani

Committee Member

Dr.Joya Chandra

Committee Member

Dr.Jonathan Kurie

Committee Member

Dr.Zahid Siddik

Committee Member

Dr.Rama Soundararajan

Abstract

Abstract

GSK3β regulates Epithelial-Mesenchymal-Transition and Cancer Stem Cell properties and is a novel drug target for Triple-Negative Breast Cancer.

Geraldine Vidhya Raja, MS.

Advisory Professor: Sendurai Mani, Ph.D.

Triple-Negative breast cancers (TNBCs) are highly aggressive and lack the expression of Estrogen Receptor (ER), Progesterone Receptor (PR) as well as Human Epidermal Growth Factor Receptor (HER2). Consequently, patients diagnosed with TNBCs have poor overall- and disease-free survival rates compared to other subtypes of breast cancer due to lack of targeted therapies as well as de novo or acquired chemoresistance, disease recurrence, and lack of targeted therapy. Hence it is critical to identify novel targets to treat TNBCs. TNBCs are characterized by the presence of mesenchymal-like cells, which is indicative that EMT (epithelial-mesenchymal-transition) plays an important role in the progression of this disease. EMT has also been implicated in chemoresistance, tumor recurrence and generation of cancer stem cells (CSCs). The Wnt signaling pathway has been determined to be one of the major players in EMT and CSCs. Therefore, we analyzed patient survival data to determine a correlation between the expression of Wnt components and overall survival. Of the several possible players, higher expression of GSK3β correlated with poorer overall patient survival. In support of this observation, we identified a GSK3β inhibitor, BIO, in a drug screen as one of the most potent inhibitors of EMT. Since TNBCs are enriched with mesenchymal-like cells, we treated mesenchymal cell lines with the GSK3β inhibitors and found that GSK3β inhibitors were among the few drugs that could selectively kill mesenchymal-like TNBC cells compared to epithelial-like breast cancer cells. To determine if GSK3β inhibitors specifically target mesenchymal-like cells by affecting the CSC population, we employed the mammosphere assay and analyzed the CD44hi/24lo population of these cell lines. We found that GSK3β inhibitors indeed decreased the CSC properties of the mesenchymal-like cell lines, and also decreased the expression of mesenchymal markers. Inhibition of GSK3β decreased the migratory properties suggesting that the inhibition of EMT by GSK3β inhibitor could contribute to the inhibitory effect of GSK3β on the migratory potential of the mesenchymal-like cells. Taken together, our studies demonstrate that GSK3β is a novel target for TNBCs and suggest that the GSK3β inhibitors could serve as selective inhibitors of EMT and CSC properties of the aggressive TNBCs, and may hence be ideal for combination treatment with standard-of-care drugs for women with this deadly disease.

Keywords

TNBC, EMT, CSC, GSK3B, WNT

Available for download on Wednesday, August 15, 2018

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