Use of dietary botanicals for maintaining health can be greatly enhanced through elucidation of their effects on epigenetic mechanisms, their combined impact and their efficacy at different life stages, especially early in life. Epigenetic aberrations often alter key gene expressions that are crucial in maintaining health and delaying the onset and reducing the impact of cancer. However, very little is known with respect to the impact of dietary botanicals consumed in combination early in life on epigenetic mechanisms and the risk of developing cancer. Our studies have indicated that green tea polyphenols (GTPs) and sulforaphane (SFN)-rich broccoli sprouts (BSp), administered in combination at safe levels consumable by humans, are highly effective in increasing cancer latency in mice that spontaneously develop estrogen receptor (ER)-negative [ER(-)] breast cancer and that this may be more effective when administered early in life. It is important that although most ER(+) breast cancer is relatively highly responsive to therapy once it forms, ER(-) breast cancer has high mortality rates if it is not prevented from developing. Therefore, cancer prevention approaches that reduce ER(-) breast cancer will have by far the greatest impact on the incidence of cancer fatalities. Our results indicate that the efficacy of this dietary approach depends on the ability of these botanicals to significantly impact epigenetic gene regulation. Our hypothesis is that early life consumption of combined GTPs and BSp is highly effective in neutralizing epigenomic alterations and epigenetic control of key genes that lead to ER(-) BC formation and progression. These studies will be important to determine the efficacy of botanicals at various stages of life so that their consumption will optimize the potential for cancer prevention. We do not yet fully understand the epigenetic mechanisms of these botanicals consumed at different stages of life and especially in combination as they are often consumed. Further, the impact of these botanicals on global epigenomic processes at various ages is not yet known. A major goal of this proposed investigation is to confront these persistent challenges. The incorporation of these botanicals into diets of the young is safe and could lead to important revisions of dietary regimens to increase cancer latency and to significantly reduce the incidence of ER(-) breast cancer fatalities. Novel techniques such as chromatin immunoprecipitation-genomic bisulfite sequencing (ChIP-GBS) that we invented as well as several advanced epigenomic technologies will be employed. Elucidation of the epigenetic mechanisms for cancer latency and reducing the risk of cancer will result in significant increases in the health of hundreds of thousands of individuals worldwide. This investigation will also provide essential information for identification of epigenetic biomarkers of breast cancer at different stages of life that will facilitate elucidation of the predisposition, diagnosis and prognosis of breast cancer. Most importantly, the use of safe and effective epigenetic aberration-neutralizing botanicals in early life has high translational potential for increasing the latency and reducing the impact of ER(-) breast cancer.

Public Health Relevance

Estrogen receptor-negative breast cancer is a leading cause of cancer morbidity and mortality because few treatment options exist for this often fatal disease. The goal of this application is to develop efficacious dietary regimens of epigenetic aberration-neutralizing dietary botanicals consumed at various stages of life for preventing estrogen receptor-negative breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Chemo/Dietary Prevention Study Section (CDP)
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Ross, Sharon A
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University of Alabama Birmingham
Schools of Arts and Sciences
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Paul, Bidisha; Li, Yuanyuan; Tollefsbol, Trygve O (2018) The Effects of Combinatorial Genistein and Sulforaphane in Breast Tumor Inhibition: Role in Epigenetic Regulation. Int J Mol Sci 19:
Gao, Yifeng; Tollefsbol, Trygve O (2018) Combinational Proanthocyanidins and Resveratrol Synergistically Inhibit Human Breast Cancer Cells and Impact Epigenetic?Mediating Machinery. Int J Mol Sci 19:
Daniel, Michael; Tollefsbol, Trygve O (2018) Pterostilbene down-regulates hTERT at physiological concentrations in breast cancer cells: Potentially through the inhibition of cMyc. J Cell Biochem 119:3326-3337
Martin, Samantha L; Royston, Kendra J; Tollefsbol, Trygve O (2018) The Role of Non-Coding RNAs and Isothiocyanates in Cancer. Mol Nutr Food Res 62:e1700913
Li, Yuanyuan; Buckhaults, Phillip; Li, Shizhao et al. (2018) Temporal Efficacy of a Sulforaphane-Based Broccoli Sprout Diet in Prevention of Breast Cancer through Modulation of Epigenetic Mechanisms. Cancer Prev Res (Phila) 11:451-464
Paul, Bidisha; Royston, Kendra J; Li, Yuanyuan et al. (2017) Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition. PLoS One 12:e0189756
Royston, Kendra J; Udayakumar, Neha; Lewis, Kayla et al. (2017) A Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells. Int J Mol Sci 18:
Li, Yuanyuan; Meeran, Syed M; Tollefsbol, Trygve O (2017) Combinatorial bioactive botanicals re-sensitize tamoxifen treatment in ER-negative breast cancer via epigenetic reactivation of ER? expression. Sci Rep 7:9345
Lewis, Kayla A; Tollefsbol, Trygve O (2017) The influence of an epigenetics diet on the cancer epigenome. Epigenomics 9:1153-1155