All ETDs from UAB

Advisory Committee Chair

Trygve O Tollefsbol

Advisory Committee Members

Stephen Barnes

Vithal K Ghanta

Casey D Morrow

Mickie L Powell

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Breast cancer is a major cause of cancer death among women in the United States. Current methods of chemoprevention and therapy have cytotoxic effects and have several short-term and long-term side effects. Therefore, the use of natural dietary bioactive compounds has gained prominence as safe and effective agents of chemoprevention and therapy. Genistein (GE), an isoflavone found in soy products, has been shown to exhibit several anticancer properties, particularly as an epigenetic modifier. We have observed that GE has the ability to alter the gut microbiome of germ-free mice humanized with fecal transplants from breast cancer patients undergoing chemotherapy. We have also observed that supplementation with GE can reduce tumor volume, tumor weight and increase latency in mice with human microbiome compared to mice on a control diet. In addition, our in vitro and in vivo findings indicate that GE when used in combination with sulforaphane (SFN), an isothiocyanate from cruciferous vegetables, is much more effective in reducing the viability of breast cancer cells than when they are administered alone. We have demonstrated that the combination of GE and SFN down-regulates KLF4 levels which play an important role in breast cancer stem cell formation. GE and SFN also down-regulate hTERT, HDAC2 and HDAC3 levels which are known to act in concert with KLF4. In vivo studies in mice further strengthen our hypothesis, where mice fed the combination diet of GE and SFN-rich broccoli sprouts had increased tumor latency and significantly reduced tumor volume when compared to the mice on a control diet or single administration of GE or SFN. Collectively, our studies provide support for the role of bioactive dietary compounds, like GE and SFN, as safe and effective agents of chemoprevention and therapy.

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