Principal Investigator

Trygve O
Tollefsbol
Awardee Organization

University Of Alabama At Birmingham
United States

Fiscal Year
2024
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Combinatorial epigenetic-based prevention of breast cancer

Combinatorial dietary approaches to prevent highly fatal estrogen receptor-negative [ER(-)] breast cancer (BC) can offer many advantages over single-agent approaches, most notably the potential for greater efficacy without increased risk of toxicity. We have shown that combined green tea polyphenols that inhibit DNA methyltransferases and sulforaphane in broccoli sprouts that inhibits histone deacetylases can significantly delay ER(-) BC initiation and impede its progression at practical and safe dietary levels. Our results have also shown that the epigenetic machinery is mechanistically important to the efficacy of ER(-) BC prevention by these diets. Maternal or paternal consumption of this combinatorial regimen can lead to increased latency and reduced tumor growth in ER(-) BC offspring that have consumed a control diet. Our field-driving studies show for the first time that this combinatorial diet impacts the epigenome and gene expression of gametes strongly supporting transgenerational epigenetic effects. Our hypothesis is that combinatorial green tea polyphenols and sulforaphane-enriched broccoli sprout diets can extend their epigenetic-neutralizing ER(-) BC preventive effects from one generation to another either through transplacental effects or through transgenerational effects. These studies will be important to resolving the generational efficacy of combinatorial cancer prevention and the epigenetic mechanisms through which this effect is mediated. Since our preliminary findings have indicated that consumption of this combinatorial diet can operate through the paternal as well as maternal lineage to prevent ER(-) BC in control-fed female offspring, this strongly suggests that the gametogenic epigenetic changes we have discovered have mechanistic importance for transgenerational effects in addition to transplacental effects in mothers fed this combinatorial diet. The paternal effects on epigenetic control of key tumor-related genes by this combinatorial epigenetic-modulating diet will contribute significantly to elucidation of the mechanisms through which this diet confers preventive effects on ER(-) BC. One of the goals of this proposed innovative investigation is to resolve the generational ER(-) BC cancer preventive impact of combinatorial epigenetic-modulating green tea polyphenols and sulforaphane-enriched broccoli sprouts and the epigenetic and epigenomic mechanisms responsible for their efficacy. This proposed investigation will have considerable impact in that the consumption of a combined epigenetic-modulating diet by either the mother or father to delay and reduce ER(-) BC in their offspring would have broad implications for new perspectives for cancer prevention. Further, ER(-) BC is often recalcitrant to conventional modes of cancer therapy which significantly increases the importance of means to facilitate its prevention. Novel approaches to reducing the risk of ER(-) BC through maternal and/or paternal consumption of this combinatorial diet would contribute significantly to enhanced ER(-) BC prevention and perhaps preventive control of other cancers worldwide.

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
  • Royston KJ, Tollefsbol TO. The Epigenetic Impact of Cruciferous Vegetables on Cancer Prevention. Current pharmacology reports. 2015 Feb 1;1(1):46-51. PMID: 25774338
  • 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
  • Lewis KA, Tollefsbol TO. Regulation of the Telomerase Reverse Transcriptase Subunit through Epigenetic Mechanisms. Frontiers in genetics. 2016 May 9;7:83. doi: 10.3389/fgene.2016.00083. eCollection 2016. PMID: 27242892
  • Dates CR, Tollefsbol TO. Transforming Cancer Epigenetics Using Nutritive Approaches and Noncoding RNAs. Current cancer drug targets. 2018;18(1):32-38. PMID: 28176654
  • Saldanha SN, Kala R, Tollefsbol TO. Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate. Experimental cell research. 2014 May 15;324(1):40-53. Epub 2014 Feb 8. PMID: 24518414
  • Li Y, Saldanha SN, Tollefsbol TO. Impact of epigenetic dietary compounds on transgenerational prevention of human diseases. The AAPS journal. 2014 Jan;16(1):27-36. Epub 2013 Oct 11. PMID: 24114450
  • 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
  • Kala R, Shah HN, Martin SL, Tollefsbol TO. Epigenetic-based combinatorial resveratrol and pterostilbene alters DNA damage response by affecting SIRT1 and DNMT enzyme expression, including SIRT1-dependent γ-H2AX and telomerase regulation in triple-negative breast cancer. BMC cancer. 2015 Oct 12;15:672. PMID: 26459286
  • Peek GW, Tollefsbol TO. Combinatorial PX-866 and Raloxifene Decrease Rb Phosphorylation, Cyclin E2 Transcription, and Proliferation of MCF-7 Breast Cancer Cells. Journal of cellular biochemistry. 2016 Jul;117(7):1688-96. Epub 2015 Dec 28. PMID: 26660119
  • Li Y, Tollefsbol TO. Age-related epigenetic drift and phenotypic plasticity loss: implications in prevention of age-related human diseases. Epigenomics. 2016 Dec;8(12):1637-1651. Epub 2016 Nov 24. PMID: 27882781
  • 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
  • Paul B, Barnes S, Demark-Wahnefried W, Morrow C, Salvador C, Skibola C, Tollefsbol TO. Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clinical epigenetics. 2015 Oct 16;7:112. doi: 10.1186/s13148-015-0144-7. eCollection 2015. PMID: 26478753
  • Saldanha SN, Royston KJ, Udayakumar N, Tollefsbol TO. Epigenetic Regulation of Epidermal Stem Cell Biomarkers and Their Role in Wound Healing. International journal of molecular sciences. 2015 Dec 24;17. (1). PMID: 26712738
  • 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
  • Gao Y, Tollefsbol TO. Impact of Epigenetic Dietary Components on Cancer through Histone Modifications. Current medicinal chemistry. 2015;22(17):2051-64. PMID: 25891109
  • 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
  • Lewis KA, Jordan HR, Tollefsbol TO. Effects of SAHA and EGCG on Growth Potentiation of Triple-Negative Breast Cancer Cells. Cancers. 2018 Dec 27;11. (1). PMID: 30591655
  • 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
  • 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
  • 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
  • Li Y, Buckhaults P, Cui X, Tollefsbol TO. Combinatorial epigenetic mechanisms and efficacy of early breast cancer inhibition by nutritive botanicals. Epigenomics. 2016 Aug;8(8):1019-37. Epub 2016 Aug 1. PMID: 27478970
  • 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
  • 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
  • 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
  • Sinha S, Shukla S, Khan S, Tollefsbol TO, Meeran SM. Epigenetic reactivation of p21CIP1/WAF1 and KLOTHO by a combination of bioactive dietary supplements is partially ERα-dependent in ERα-negative human breast cancer cells. Molecular and cellular endocrinology. 2015 May 5;406:102-14. Epub 2015 Feb 25. PMID: 25725373
  • 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
  • Daniel M, Tollefsbol TO. Epigenetic linkage of aging, cancer and nutrition. The Journal of experimental biology. 2015 Jan 1;218(Pt 1):59-70. PMID: 25568452
  • Krakowsky RH, Tollefsbol TO. Impact of Nutrition on Non-Coding RNA Epigenetics in Breast and Gynecological Cancer. Frontiers in nutrition. 2015 May 27;2:16. doi: 10.3389/fnut.2015.00016. eCollection 2015. PMID: 26075205
  • 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
  • Peek GW, Tollefsbol TO. Down-regulation of hTERT and Cyclin D1 transcription via PI3K/Akt and TGF-β pathways in MCF-7 Cancer cells with PX-866 and Raloxifene. Experimental cell research. 2016 May 15;344(1):95-102. Epub 2016 Mar 23. PMID: 27017931
  • 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, 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
  • Peek GW, Tollefsbol TO. Erratum to "Down-regulation of hTERT and Cyclin D1 transcription via PI3K/Akt and TGF-β pathways in MCF-7 cancer cells with PX-866 and Raloxifene" [Exp. Cell Res. 344 (2016) 95-102]. Experimental cell research. 2016 Jul 15;345(2):255. Epub 2016 Jun 2. PMID: 27265745
  • 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 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
  • 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
  • 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 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
  • 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
  • Kala R, Tollefsbol TO. A Novel Combinatorial Epigenetic Therapy Using Resveratrol and Pterostilbene for Restoring Estrogen Receptor-α (ERα) Expression in ERα-Negative Breast Cancer Cells. PloS one. 2016 May 9;11(5):e0155057. doi: 10.1371/journal.pone.0155057. eCollection 2016. PMID: 27159275
  • 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
  • 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
  • Rahman MM, Wu H, Tollefsbol TO. A novel combinatorial approach using sulforaphane- and withaferin A-rich extracts for prevention of estrogen receptor-negative breast cancer through epigenetic and gut microbial mechanisms. Scientific reports. 2024 May 27;14(1):12091. PMID: 38802425