All ETDs from UAB

Advisory Committee Chair

Trygve O Tollefsbol

Advisory Committee Members

Wendy Demark-Wahnefried

Yuanyuan Li

Mickie L Powell

Thane Wibbels

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Breast cancer is currently the most commonly diagnosed and second most common cause of cancer related deaths among women in the United States. Although overall breast cancer death rates have dropped over the past decades, current chemotherapeutic methods often prove ineffective and result in off-target, cytotoxic effects. Recently, the use of natural, dietary compounds as agents of chemoprevention and therapy has become increasingly provocative. Pterostilbene (PT), a stilbenoid found largely in the blueberries, has been shown to exhibit both antioxidant and antiproliferative effects in a variety of cancer types. We observed that PT, at physiological concentrations, inhibits the proliferation, cell cycle progression and colony forming potential of breast cancer cells. Moreover, PT was shown to down-regulate the human telomerase reverse transcriptase (hTERT), which is dysregulated in approximately 90% of human cancers. cMyc, an oncogene and activator of hTERT, was also shown to be down-regulated upon treatment with PT, although a complete mechanism of its inhibition and down-regulation of hTERT, after treatment with pterostilbene, has not been solidified. The phosphorylation and subsequent activation of the Akt/mTOR/p70S6K pathway is another common characteristic of oncogenesis. We were also able to show that PT further inhibits breast cancer through the inhibition of phosphorylated Akt, mTOR and p70S6K. Treatment of breast cancer cells with PT, at physiological concentrations, decreased the protein expressions and activity levels of Akt, mTOR and p70S6K in a dose-dependent manner. In addition, when compared to the levels of inhibition exhibited by wortmannin, an inhibitor of the Akt pathway, and by rapamycin, a potent inhibitor of mTOR, inhibition was mimicked and in some cases exceeded by PT treatments. Collectively, our study provides solid findings that further support the potential use of natural compounds, like PT, as chemopreventive and chemotherapeutic agents, either singly or in combination with current therapies.

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