Advisory Committee Chair
Trygve O Tollefbol
Advisory Committee Members
Jeremy B Foote
Yuanyuan Li
Mickie L Powell
Matthew L Stoll
Document Type
Dissertation
Date of Award
2022
Degree Name by School
Doctor of Philosophy (PhD) College of Arts and Sciences
Abstract
Breast cancer is the second leading causes of mortality among women living in the United States, representing a major public health issue. The current chemoprevention therapies can result into various adverse effects. Therefore, the use of dietary bioactive compounds has been of great interest due to their safer, non-toxic and efficacious properties. Sulforaphane (SFN) is an isothiocyanate found in various cruciferous vegetables such as broccoli sprouts (BSp) and green-tea polyphenols (GTPs) contain a major polyphenol, (-)-epigallocatechin-3-gallate (EGCG). These compounds have been shown to exhibit several anticancer properties especially as an epigenetic modifier. We investigated the efficacy of BSp or GTPs or their combination at two specific life stages, beginning in early life (BE) or life-long from conception (LC) in Her2/neu transgenic mouse. The combination of BSp and GTPs had maximum effect on inhibiting tumor growth volume and in increasing tumor latency. We have observed that dietary groups have the ability to alter the gut microbiome and levels of key metabolites such as short-chain fatty acids (SCFAs) in transgenic mice. We also investigated the efficacy of dietary genistein (GE) which is an isoflavone found in soy products that participates in epigenetic regulation against numerous cancers. The administration of GE in two established triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) mouse models, BCM-3204 and TM00091, displayed suppressing effects on tumor growth. The iv further mechanistic evaluation revealed several differentially expressed genes (DEGs) and global epigenetic changes in response to dietary GE. In addition, our in vitro findings indicate that GE when used in combination with SFN and sodium butyrate (NaB), a short-chain fatty acid (SCFA) produced by gut microbiota from fermentation of dietary fiber, is much more effective in reducing the viability of breast cancer cells than when they are administered alone. We demonstrated that the di-combinations (SFN-GE, SFN-NaB and GE-NaB) and tri-combination also had higher impact in down-regulation of various epigenetic-associated genes and enzymes. Overall, our studies provide support for the role of bioactive dietary compounds such as BSp/SFN, GTPs, GE and NaB as safe and effective agents of breast chemoprevention and therapy.
Recommended Citation
Sharma, Manvi, "Role of Dietary Compounds on Modulation of Epigenetic Mechanisms and Gut Microbiota in Prevention of Breast Cancer" (2022). All ETDs from UAB. 332.
https://digitalcommons.library.uab.edu/etd-collection/332