Program Official

Principal Investigator

Trygve O
Tollefsbol
Awardee Organization

University Of Alabama At Birmingham
United States

Fiscal Year
2021
Activity Code
R01
Project End Date

Early life prevention of breast cancer with combined epigenetic botanicals

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.

Publications

  • Daniel M, Tollefsbol TO. Pterostilbene down-regulates hTERT at physiological concentrations in breast cancer cells: Potentially through the inhibition of cMyc. Journal of cellular biochemistry. 2018 Apr;119(4):3326-3337. Epub 2017 Dec 26. PMID: 29125889
  • Arora I, Sharma M, Li S, Crowley M, Crossman DK, Li Y, Tollefsbol TO. An integrated analysis of the effects of maternal broccoli sprouts exposure on transcriptome and methylome in prevention of offspring mammary cancer. PloS one. 2022 Mar 9;17(3):e0264858. doi: 10.1371/journal.pone.0264858. eCollection 2022. PMID: 35263365
  • Paul B, Li Y, Tollefsbol TO. The Effects of Combinatorial Genistein and Sulforaphane in Breast Tumor Inhibition: Role in Epigenetic Regulation. International journal of molecular sciences. 2018 Jun 13;19. (6). PMID: 29899271
  • Martin SL, Kala R, Tollefsbol TO. Mechanisms for the Inhibition of Colon Cancer Cells by Sulforaphane through Epigenetic Modulation of MicroRNA-21 and Human Telomerase Reverse Transcriptase (hTERT) Down-regulation. Current cancer drug targets. 2018;18(1):97-106. PMID: 28176652
  • Dates CR, Tollefsbol TO. Transforming Cancer Epigenetics Using Nutritive Approaches and Noncoding RNAs. Current cancer drug targets. 2018;18(1):32-38. PMID: 28176654
  • Arora I, Sharma M, Sun LY, Tollefsbol TO. The Epigenetic Link between Polyphenols, Aging and Age-Related Diseases. Genes. 2020 Sep 18;11. (9). PMID: 32962067
  • Brane AC, Tollefsbol TO. Targeting Telomeres and Telomerase: Studies in Aging and Disease Utilizing CRISPR/Cas9 Technology. Cells. 2019 Feb 21;8. (2). PMID: 30795542
  • Arora I, Sharma M, Tollefsbol TO. Combinatorial Epigenetics Impact of Polyphenols and Phytochemicals in Cancer Prevention and Therapy. International journal of molecular sciences. 2019 Sep 14;20. (18). PMID: 31540128
  • Li S, Chen M, Wu H, Li Y, Tollefsbol TO. Maternal Epigenetic Regulation Contributes to Prevention of Estrogen Receptor-negative Mammary Cancer with Broccoli Sprout Consumption. Cancer prevention research (Philadelphia, Pa.). 2020 May;13(5):449-462. Epub 2020 Mar 17. PMID: 32184225
  • Wu H, Van Der Pol WJ, Dubois LG, Morrow CD, Tollefsbol TO. Dietary Supplementation of Inulin Contributes to the Prevention of Estrogen Receptor-Negative Mammary Cancer by Alteration of Gut Microbial Communities and Epigenetic Regulations. International journal of molecular sciences. 2023 May 19;24. (10). PMID: 37240357
  • Sharma M, Arora I, Stoll ML, Li Y, Morrow CD, Barnes S, Berryhill TF, Li S, Tollefsbol TO. Nutritional combinatorial impact on the gut microbiota and plasma short-chain fatty acids levels in the prevention of mammary cancer in Her2/neu estrogen receptor-negative transgenic mice. PloS one. 2020 Dec 31;15(12):e0234893. doi: 10.1371/journal.pone.0234893. eCollection 2020. PMID: 33382695
  • Chen M, Li S, Srinivasasainagendra V, Sharma M, Li Z, Tiwari H, Tollefsbol TO, Li Y. Maternal soybean genistein on prevention of later-life breast cancer through inherited epigenetic regulations. Carcinogenesis. 2022 Apr 25;43(3):190-202. PMID: 35084457
  • Royston KJ, Udayakumar N, Lewis K, Tollefsbol TO. A Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells. International journal of molecular sciences. 2017 May 19;18. (5). PMID: 28534825
  • Arora I, Tollefsbol TO. Computational methods and next-generation sequencing approaches to analyze epigenetics data: Profiling of methods and applications. Methods (San Diego, Calif.). 2021 Mar;187:92-103. Epub 2020 Sep 14. PMID: 32941995
  • Paul B, Royston KJ, Li Y, Stoll ML, Skibola CF, Wilson LS, Barnes S, Morrow CD, Tollefsbol TO. Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition. PloS one. 2017 Dec 21;12(12):e0189756. doi: 10.1371/journal.pone.0189756. eCollection 2017. PMID: 29267377
  • Arora I, Li Y, Sharma M, Crowley MR, Crossman DK, Li S, Tollefsbol TO. Systematic integrated analyses of methylomic and transcriptomic impacts of early combined botanicals on estrogen receptor-negative mammary cancer. Scientific reports. 2021 May 4;11(1):9481. PMID: 33947955
  • Li S, Wu H, Tollefsbol TO. Combined Broccoli Sprouts and Green Tea Polyphenols Contribute to the Prevention of Estrogen Receptor-Negative Mammary Cancer via Cell Cycle Arrest and Inducing Apoptosis in HER2/neu Mice. The Journal of nutrition. 2021 Jan 4;151(1):73-84. PMID: 33188406
  • Lewis KA, Tollefsbol TO. The influence of an epigenetics diet on the cancer epigenome. Epigenomics. 2017 Sep;9(9):1153-1155. Epub 2017 Aug 11. PMID: 28799802
  • Royston KJ, Paul B, Nozell S, Rajbhandari R, Tollefsbol TO. Withaferin A and sulforaphane regulate breast cancer cell cycle progression through epigenetic mechanisms. Experimental cell research. 2018 Jul 1;368(1):67-74. Epub 2018 Apr 22. PMID: 29689276
  • Martin SL, Royston KJ, Tollefsbol TO. The Role of Non-Coding RNAs and Isothiocyanates in Cancer. Molecular nutrition & food research. 2018 Sep;62(18):e1700913. Epub 2018 May 28. PMID: 29532604
  • Sharma M, Tollefsbol TO. Combinatorial epigenetic mechanisms of sulforaphane, genistein and sodium butyrate in breast cancer inhibition. Experimental cell research. 2022 Jul 1;416(1):113160. Epub 2022 Apr 18. PMID: 35447103
  • Brane A, Arora I, Tollefsbol TO. Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes. Cancers. 2023 Jan 21;15. (3). PMID: 36765634
  • Ganguly S, Arora I, Tollefsbol TO. Impact of Stilbenes as Epigenetic Modulators of Breast Cancer Risk and Associated Biomarkers. International journal of molecular sciences. 2021 Sep 17;22. (18). PMID: 34576196
  • Steed KL, Jordan HR, Tollefsbol TO. SAHA and EGCG Promote Apoptosis in Triple-negative Breast Cancer Cells, Possibly Through the Modulation of cIAP2. Anticancer research. 2020 Jan;40(1):9-26. PMID: 31892549
  • Li Y, Buckhaults P, Li S, Tollefsbol T. Temporal Efficacy of a Sulforaphane-Based Broccoli Sprout Diet in Prevention of Breast Cancer through Modulation of Epigenetic Mechanisms. Cancer prevention research (Philadelphia, Pa.). 2018 Aug;11(8):451-464. Epub 2018 May 15. PMID: 29764806
  • Wu H, Ganguly S, Tollefsbol TO. Modulating Microbiota as a New Strategy for Breast Cancer Prevention and Treatment. Microorganisms. 2022 Aug 27;10. (9). PMID: 36144329
  • Akinyemiju T, Jones K, Gupta A, Oyekunle T, Saraiya V, Deveaux A, Salako O, Hall A, Alatise O, Ogun G, Adeniyi A, Ayandipo O, Olajide T, Olasehinde O, Arowolo O, Adisa A, Afuwape O, Olusanya A, Adegoke A, Tollefsbol TO, Arnett D, H3 Africa Kidney Research Network, Daramola A, Ajayi S, Raji Y, Olanrewaju T, Osafo C, Ulasi I, Asinobi A, Winkler CA, Burke D, Arogundade F, Ekem I, Plange-Rhule J, Mamven M, Mate-Kole M, Amodu O, Cooper R, Antwi S, Adeyemo A, Ilori T, Adabayeri V, Nyarko A, Ghansah A, Amos-Abanyie EK, Akyaw PA, Kimmel PL, Salako BL, Parekh RS, Tayo B, Gbadegesin R, Boehnke M, Lyons R, Brosius FC, Clauw D, Adindu C, Bewaji C, Tannor EK, Okyere P, Ijoma C, Tiffin N, Gamiedien J, Hildebrandt F, Odenigbo C, Jisieike-Onuigbo N, Modebe I, Abdu A, Obiagwu P, Okoye O, Solarin A, Amira T, Esezobor C, Makusidi M, Saraf S, Gordeuk V, Ashuntangtang G, Guenkam G, Kazi F, Adedoyin O, McCullough M, Nourse P, Okafor U, Anigilaje E, Ikpebe P, Odetunde T, Mbanefo N, Olowu W, Tindana P, Awobusuyi O, Ogedegbe O, Olabisi O, Skorecki K, Adebowale A, Kretzler M, Hodgin J, Adu D, Ojo A, Boima V. Association of body composition with odds of breast cancer by molecular subtype: analysis of the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Nigerian Women (MEND) study. BMC cancer. 2021 Sep 25;21(1):1051. PMID: 34563146
  • Sharma M, Li Y, Stoll ML, Tollefsbol TO. The Epigenetic Connection Between the Gut Microbiome in Obesity and Diabetes. Frontiers in genetics. 2020 Jan 15;10:1329. doi: 10.3389/fgene.2019.01329. eCollection 2019. PMID: 32010189
  • Li S, Tollefsbol TO. DNA methylation methods: Global DNA methylation and methylomic analyses. Methods (San Diego, Calif.). 2021 Mar;187:28-43. Epub 2020 Oct 9. PMID: 33039572
  • Rahman MM, Brane AC, Tollefsbol TO. MicroRNAs and Epigenetics Strategies to Reverse Breast Cancer. Cells. 2019 Oct 8;8. (10). PMID: 31597272
  • Li Y, Meeran SM, Tollefsbol TO. Combinatorial bioactive botanicals re-sensitize tamoxifen treatment in ER-negative breast cancer via epigenetic reactivation of ERα expression. Scientific reports. 2017 Aug 24;7(1):9345. PMID: 28839265
  • Arora I, Li S, Crowley MR, Li Y, Tollefsbol TO. Genome-Wide Analysis on Transcriptome and Methylome in Prevention of Mammary Tumor Induced by Early Life Combined Botanicals. Cells. 2022 Dec 21;12. (1). PMID: 36611809
  • Sharma M, Arora I, Chen M, Wu H, Crowley MR, Tollefsbol TO, Li Y. Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms. Nutrients. 2021 Nov 4;13. (11). PMID: 34836197
  • Rahman MM, Tollefsbol TO. Targeting cancer epigenetics with CRISPR-dCAS9: Principles and prospects. Methods (San Diego, Calif.). 2021 Mar;187:77-91. Epub 2020 Apr 18. PMID: 32315755
  • Akinyemiju T, Salako O, Daramola A, Alatise O, Adeniyi A, Ogun G, Ayandipo O, Olajide T, Olasehinde O, Arowolo O, Adisa A, Afuwape O, Olusanya A, Adegoke A, Ojo A, Tollefsbol T, Arnett D. Collaborative Molecular Epidemiology Study of Metabolic Dysregulation, DNA Methylation, and Breast Cancer Risk Among Nigerian Women: MEND Study Objectives and Design. Journal of global oncology. 2019 Jun;5:1-9. PMID: 31194608
  • Gupta A, Jones K, Deveaux A, Bevel M, Salako O, Daramola A, Hall A, Alatise O, Ogun G, Adeniyi A, Ojo A, Ayandipo O, Olajide T, Olasehinde O, Arowolo O, Adisa A, Afuwape O, Olusanya A, Adegoke A, Tollefsbol TO, Arnett D, Newgard CB, Akinyemiju T. Association of Life-Course Educational Attainment and Breast Cancer Grade in the MEND Study. Annals of global health. 2021 Jul 7;87(1):59. doi: 10.5334/aogh.3142. eCollection 2021. PMID: 34277361
  • García-Giménez JL, Seco-Cervera M, Tollefsbol TO, Romá-Mateo C, Peiró-Chova L, Lapunzina P, Pallardó FV. Epigenetic biomarkers: Current strategies and future challenges for their use in the clinical laboratory. Critical reviews in clinical laboratory sciences. 2017 Nov-Dec;54(7-8):529-550. Epub 2017 Dec 11. PMID: 29226748
  • Witt BL, Tollefsbol TO. Molecular, Cellular, and Technical Aspects of Breast Cancer Cell Lines as a Foundational Tool in Cancer Research. Life (Basel, Switzerland). 2023 Dec 8;13. (12). PMID: 38137912
  • Li Y. Epigenetic Mechanisms Link Maternal Diets and Gut Microbiome to Obesity in the Offspring. Frontiers in genetics. 2018 Aug 27;9:342. doi: 10.3389/fgene.2018.00342. eCollection 2018. PMID: 30210530
  • Li S, Wu H, Chen M, Tollefsbol TO. Paternal Combined Botanicals Contribute to the Prevention of Estrogen Receptor-Negative Mammary Cancer in Transgenic Mice. The Journal of nutrition. 2023 Jul;153(7):1959-1973. Epub 2023 May 3. PMID: 37146973
  • Chen M, Li S, Arora I, Yi N, Sharma M, Li Z, Tollefsbol TO, Li Y. Maternal soybean diet on prevention of obesity-related breast cancer through early-life gut microbiome and epigenetic regulation. The Journal of nutritional biochemistry. 2022 Dec;110:109119. Epub 2022 Aug 3. PMID: 35933021
  • Gupta A, Oyekunle T, Salako O, Daramola A, Alatise O, Ogun G, Adeniyi A, Deveaux A, Saraiya V, Hall A, Ayandipo O, Olajide T, Olasehinde O, Arowolo O, Adisa A, Afuwape O, Olusanya A, Adegoke A, Tollefsbol TO, Arnett D, Muehlbauer MJ, Newgard CB, H3 Africa Kidney Research Network, Akinyemiju T. Association of high-sensitivity C-reactive protein and odds of breast cancer by molecular subtype: analysis of the MEND study. Oncotarget. 2021 Jun 22;12(13):1230-1242. doi: 10.18632/oncotarget.27991. eCollection 2021 Jun 22. PMID: 34194621
  • Gao Y, Tollefsbol TO. Combinational Proanthocyanidins and Resveratrol Synergistically Inhibit Human Breast Cancer Cells and Impact Epigenetic⁻Mediating Machinery. International journal of molecular sciences. 2018 Jul 27;19. (8). PMID: 30060527
  • Li S, Chen M, Li Y, Tollefsbol TO. Prenatal epigenetics diets play protective roles against environmental pollution. Clinical epigenetics. 2019 May 16;11(1):82. PMID: 31097039