All ETDs from UAB

Advisory Committee Chair

Trygve O Tollefsbol

Advisory Committee Members

Farah Lubin

Helen Kim

Shahid M Mukhtar

Nicole Riddle

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Although the majority of breast cancers are estrogen receptor (ER)-positive, progesterone receptor (PGR)-positive and/or HER2 positive, approximately 20% of them are triple-negative and lack ER, PGR and HER2 protein expression. These cancers are robust and hard to treat with conventional hormone therapies. The plant-based dietary compounds resveratrol and pterostilbene (a dimethyl derivative of resveratrol) have been shown to modulate the growth of cancer cells individually via affecting genetic and epigenetic profiles, but none of the studies to date have addressed the effects of these two compounds in combination in targeting triple-negative breast cancers (TNBC). We have discovered a synergistic effect of these two compounds when administered in combination in targeting the viability of TNBC at concentrations close to physiologically achievable doses. The effects were further found to be dose- and time-dependent in inhibiting the growth of TNBC cells via inhibiting the expression of SIRT1. This down regulation of SIRT1 further resulted in a significant reduction in DNA damage response (DDR) and telomerase expression, which was indicated by a significant increase in apoptosis in the TNBC cells. In addition, the combination also resulted in a significant increase in the expression of ERα in ERα-negative breast cancer cells. This increase in expression was due a time-dependent enrichment of acetyl histone H3lysine9 (H3K9), acetyl H3 and H4 active chromatin markers in the ERα promoter region as well as a global decline in 5-methylcytosine (5-mC) levels. To further test the functional reactivation of ERα, MDA-MB-157 TNBC cells after combinational treatments were exposed to 48 h of traditional tamoxifen therapy and were found to be sensitive to this treatment, hence highlighting a novel discovery with these two compounds in combination. The combination used in this study was safe and non-toxic to control MCF10A non-tumorigenic breast epithelial cells. Collectively, these findings provide new and safer ways to target TNBCs with the use of these two phytochemicals as a novel therapeutic approach and/or administered as an adjuvant therapy along with currently available tamoxifen treatments.

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