Extra Virgin Olive Oil and Corn Oil and Epigenetic Patterns in Breast Cancer

  • Raquel MoralEmail author
  • Eduard Escrich
Reference work entry


Breast cancer is the leading neoplasia in women worldwide. Nutrition and especially dietary lipids can influence mammary carcinogenesis through multiple mechanisms. This works aims to get insight into the effects of two common oils, extra virgin olive oil (EVOO) and corn oil, on mammary carcinogenesis and the molecular mechanisms of such effects. The administration of a diet high in corn oil (HCO) from weaning had a clear stimulating effect on 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis, increasing the morphological and clinical degree of tumor malignancy, while a high-EVOO diet has a weak tumor-enhancing effect. The HCO diet modified gene expression profiles in mammary gland and tumors, downregulating genes with a role in apoptosis and immune system. On the contrary, the high-EVOO diet mainly modulated genes with a role in metabolism. These effects may be a consequence of an influence on the epigenetic machinery. Thus, the high-EVOO diet increased global DNA methylation in the mammary gland, mainly around puberty, and also in experimental mammary tumors. In relation to gene-specific methylation, the HCO diet, but not the high EVOO one, increased the total DNA methyltransferase activity in mammary glands and tumors, concomitantly with the increase in Rassf1a and Timp3 promoter methylation. Both high-fat diets may influence the modification of histones (the levels of H3K4me2, H3K27me3, H4K16ac, and H4K20me3), especially in the mammary gland. Although there is little data reported at other epigenetic levels, the differential effects of the diets are likely to be also due to different modification of microRNA patterns. Considering the unspecific tumor-promoting effect of all high-fat diets, the results suggest some beneficial effect of EVOO that counteracts the deleterious influence of excessive fat intake. The EVOO minor components may have a key role in such beneficial effects modulating, at least in part, the epigenetic machinery.


Breast cancer Mediterranean diet High-fat diets Extra virgin olive oil N-6 PUFA DMBA Experimental mammary tumors Mammary gland Global DNA methylation DNMT activity Rassf1a Timp3 Histone H3 Histone H4 

List of Abbreviations




DNA methyltransferase


Extra virgin olive oil


Dimethylation at lysine 4 of histone H3


Trimethylation at lysine 27 of histone H3


Acetylation at lysine 16 of histone H4


Trimethylation at lysine 20 of histone H4


High corn oil


Histone deacetylase


High extra virgin olive oil


Low fat


Monounsaturated fatty acid


Polyunsaturated fatty acid



Research in the authors’ laboratory is funded by grants from “Plan Nacional de I+D+I” (AGL2006-07691; AGL2011-24778); “Fundación Patrimonio Comunal Olivarero (FPCO)” (FPCO2008-165.396; FPCO2013-CF611.084); “Agencia para el Aceite de Oliva del Ministerio de Medio Ambiente y de Medio Rural y Marino” (AAO2008-165.471); “Organización Interprofesional del Aceite de Oliva Español (OIAOE)” (OIP2009-CD165.646); “Departaments d’Agricultura, Alimentació i Acció Rural, i de Salut de la Generalitat de Catalunya” (GC2010-165.000); and FPCO and OIAOE (FPCO-OIP2016-CF614.087). The sponsors had no role in study designs, data collection and analyses, interpretation of results, preparation of the manuscript, and the decision to submit the manuscript for publication or the writing of the manuscript. The authors are grateful to I. Costa, R. Escrich, C. Rodríguez-Miguel, M.C. Ruiz de Villa, M. Solanas, and E. Vela for their collaboration in these studies.


  1. Burdge GC, Lillycrop KA (2014) Fatty acids and epigenetics. Curr Opin Clin Nutr Metab Care 17:156–161CrossRefGoogle Scholar
  2. Costa I, Solanas M, Escrich E (2002) Histopathologic characterization of mammary neoplastic lesions induced with 7,12-dimethylbenz(alpha)anthracene in the rat: a comparative analysis with human breast tumors. Arch Pathol Lab Med 126:915–927PubMedGoogle Scholar
  3. Couto E, Boffetta P, Lagiou P et al (2011) Mediterranean dietary pattern and cancer risk in the EPIC cohort. Br J Cancer 104:1493–1499CrossRefGoogle Scholar
  4. D’Amore S, Vacca M, Cariello M et al (2016) Genes and miRNA expression signatures in peripheral blood mononuclear cells in healthy subjects and patients with metabolic syndrome after acute intake of extra virgin olive oil. Biochim Biophys Acta 1861:1671–1680CrossRefGoogle Scholar
  5. Davidson LA, Wang N, Shah MS et al (2009) n-3 polyunsaturated fatty acids modulate carcinogen-directed non-coding microRNA signatures in rat colon. Carcinogenesis 30:2077–2084CrossRefGoogle Scholar
  6. Di Francesco A, Falconi A, Di Germanio C et al (2015) Extravirgin olive oil up-regulates CB1 tumor suppressor gene in human colon cancer cells and in rat colon via epigenetic mechanisms. J Nutr Biochem 26:250–258CrossRefGoogle Scholar
  7. Dimri M, Bommi PV, Sahasrabuddhe AA et al (2010) Dietary omega-3 polyunsaturated fatty acids suppress expression of EZH2 in breast cancer cells. Carcinogenesis 31:489–495CrossRefGoogle Scholar
  8. Eden A, Gaudet F, Waghmare A et al (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300:455CrossRefGoogle Scholar
  9. Escrich E (1987) Validity of the DMBA-induced mammary cancer model for the study of human breast cancer. Int J Biol Markers 2:197–206CrossRefGoogle Scholar
  10. Escrich E, Moral R, García G et al (2004) Identification of novel differentially expressed genes by the effect of a high-fat n-6 diet in experimental breast cancer. Mol Carcinog 40:73–78CrossRefGoogle Scholar
  11. Escrich E, Solanas M, Moral R (2006) Olive oil, and other dietary lipids, in cancer: experimental approaches. In: Quiles JL, Ramírez-Tortosa MC, Yaqoob P (eds) Olive oil and health. CABI Publishing, Oxford, pp 317–374CrossRefGoogle Scholar
  12. Escrich E, Solanas M, Moral R et al (2011) Modulatory effects and molecular mechanisms of olive oil and other dietary lipids in breast cancer. Curr Pharm Des 17:813–830CrossRefGoogle Scholar
  13. Faragó N, Fehér LZ, Kitajka K et al (2011) MicroRNA profile of polyunsaturated fatty acid treated glioma cells reveal apoptosis-specific expression changes. Lipids Health Dis 10:173CrossRefGoogle Scholar
  14. Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386CrossRefGoogle Scholar
  15. Fraga MF, Ballestar E, Villar-Garea A et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400CrossRefGoogle Scholar
  16. Greer EL, Shi Y (2012) Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 13:343–357CrossRefGoogle Scholar
  17. Han L, Ge J, Zhang L et al (2015) Sirt6 depletion causes spindle defects and chromosome misalignment during meiosis of mouse oocyte. Sci Rep 5:15366CrossRefGoogle Scholar
  18. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefGoogle Scholar
  19. Hannafon BN, Carpenter KJ, Berry WL et al (2015) Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA). Mol Cancer 14:133CrossRefGoogle Scholar
  20. Hesson LB, Cooper WN, Latif F (2007) The role of RASSF1A methylation in cancer. Dis Markers 23:73–87CrossRefGoogle Scholar
  21. Kutanzi K, Kovalchuk O (2013) Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats. Cancer Biol Ther 14:564–573CrossRefGoogle Scholar
  22. Lee WJ, Zhu BT (2006) Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. Carcinogenesis 27:269–277CrossRefGoogle Scholar
  23. Luceri C, Bigagli E, Pitozzi V et al (2017) A nutrigenomics approach for the study of anti-aging interventions: olive oil phenols and the modulation of gene and microRNA expression profiles in mouse brain. Eur J Nutr 56:865–877Google Scholar
  24. Mandal CC, Ghosh-Choudhury T, Dey N et al (2012) miR-21 is targeted by omega-3 polyunsaturated fatty acid to regulate breast tumor CSF-1 expression. Carcinogenesis 33:1897–1908CrossRefGoogle Scholar
  25. Manzanares MA, Solanas M, Moral R et al (2015) Dietary extra-virgin olive oil and corn oil differentially modulate the mRNA expression of xenobiotic-metabolizing enzymes in the liver and in the mammary gland in a rat chemically induced breast cancer model. Eur J Cancer Prev 24:215–222CrossRefGoogle Scholar
  26. Markaverich BM, Shoulars K, Rodriguez MA (2011) Luteolin regulation of estrogen signaling and cell cycle pathway genes in MCF-7 human breast cancer cells. Int J Biomed Sci 7:101–111PubMedPubMedCentralGoogle Scholar
  27. Moral R, Solanas M, Garcia G et al (2008) High corn oil and high extra virgin olive oil diets have different effects on the expression of differentiation-related genes in experimental mammary tumors. Oncol Rep 20:429–435PubMedGoogle Scholar
  28. Moral R, Escrich R, Solanas M et al (2011) Diets high in corn oil or extra-virgin olive oil provided from weaning advance sexual maturation and differentially modify susceptibility to mammary carcinogenesis in female rats. Nutr Cancer 63:410–420CrossRefGoogle Scholar
  29. Moral R, Escrich R, Solanas M et al (2016) Diets high in corn oil or extra-virgin olive oil differentially modify the gene expression profile of the mammary gland and influence experimental breast cancer susceptibility. Eur J Nutr 55:1397–1409CrossRefGoogle Scholar
  30. Niu Y, DesMarais TL, Tong Z et al (2015) Oxidative stress alters global histone modification and DNA methylation. Free Radic Biol Med 82:22–28CrossRefGoogle Scholar
  31. Oliveras-Ferraros C, Fernández-Arroyo S, Vazquez-Martin A et al (2011) Crude phenolic extracts from extra virgin olive oil circumvent de novo breast cancer resistance to HER1/HER2-targeting drugs by inducing GADD45-sensed cellular stress, G2/M arrest and hyperacetylation of histone H3. Int J Oncol 38:1533–1547PubMedGoogle Scholar
  32. Ørom UA, Lim MK, Savage JE et al (2012) MicroRNA-203 regulates caveolin-1 in breast tissue during caloric restriction. Cell Cycle 11:1291–1295CrossRefGoogle Scholar
  33. Paluszczak J, Krajka-Kuźniak V, Baer-Dubowska W (2010) The effect of dietary polyphenols on the epigenetic regulation of gene expression in MCF7 breast cancer cells. Toxicol Lett 192:119–125CrossRefGoogle Scholar
  34. Quiles JL, Ramírez-Tortosa MC, Yaqoob P (eds) (2006) Olive oil and health. CABI Publishing, OxfordGoogle Scholar
  35. Radpour R, Kohler C, Haghighi MM et al (2009) Methylation profiles of 22 candidate genes in breast cancer using high-throughput MALDI-TOF mass array. Oncogene 28:2969–2978CrossRefGoogle Scholar
  36. Rahnasto-Rilla M, Kokkola T, Jarho E et al (2016) N-acylethanolamines bind to SIRT6. Chembiochem 17:77–81CrossRefGoogle Scholar
  37. Rodríguez-Miguel C, Moral R, Escrich R et al (2015) The role of dietary extra virgin olive oil and corn oil on the alteration of epigenetic patterns in the rat DMBA-induced breast cancer model. PLoS One 10:e0138980CrossRefGoogle Scholar
  38. Russo IH, Russo J (1996) Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect 104:938–967CrossRefGoogle Scholar
  39. Schulz M, Hoffmann K, Weikert C et al (2008) Identification of a dietary pattern characterized by high-fat food choices associated with increased risk of breast cancer: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. Br J Nutr 100:942–946CrossRefGoogle Scholar
  40. Sieri S, Krogh V, Ferrari P et al (2008) Dietary fat and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr 88:1304–1312PubMedGoogle Scholar
  41. Sierra MI, Fernández AF, Fraga MF (2015) Epigenetics of aging. Curr Genomics 16:435–440CrossRefGoogle Scholar
  42. Sofi F, Abbate R, Gensini GF et al (2010) Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr 92:1189–1196CrossRefGoogle Scholar
  43. Solanas M, Grau L, Moral R et al (2010) Dietary olive oil and corn oil differentially affect experimental breast cancer through distinct modulation of the p21Ras signaling and the proliferation-apoptosis balance. Carcinogenesis 31:871–879CrossRefGoogle Scholar
  44. Starlard-Davenport A, Tryndyak VP, James SR et al (2010) Mechanisms of epigenetic silencing of the Rassf1a gene during estrogen-induced breast carcinogenesis in ACI rats. Carcinogenesis 31:376–381CrossRefGoogle Scholar
  45. Tezcan G, Tunca B, Bekar A et al (2014) Olea europaea leaf extract improves the treatment response of GBM stem cells by modulating miRNA expression. Am J Cancer Res 4:572–590PubMedPubMedCentralGoogle Scholar
  46. Tseng TH, Chien MH, Lin WL et al (2017) Inhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21WAF1/CIP1 expression. Environ Toxicol 32:434–444Google Scholar
  47. Veeck J, Esteller M (2010) Breast cancer epigenetics: from DNA methylation to microRNAs. J Mammary Gland Biol Neoplasia 15:5–17CrossRefGoogle Scholar
  48. WCRF/AICR – World Cancer Research Fund/American Institute for Cancer Research (2007) Food, nutrition, physical activity, and the prevention of cancer: a global perspective. American Institute for Cancer Research, Washington, DCGoogle Scholar
  49. Xiao X, Shi D, Liu L et al (2011) Quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of P300 signaling. PLoS One 6:e22934CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Multidisciplinary Group for the Study of Breast Cancer, Department of Cell Biology, Physiology and Immunology, Physiology Unit, Faculty of MedicineUniversitat Autònoma de BarcelonaBarcelonaSpain

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