Nutritional Regulation of Mammary miRNome: Implications for Human Studies

  • Christine LerouxEmail author
  • Dragan Milenkovic
  • Lenha Mobuchon
  • Sandrine Le Guillou
  • Yannick Faulconnier
  • Bruce German
  • Fabienne Le Provost
Reference work entry


Mammary gland is the organ of milk component synthesis that provides the nutrients for growth and development of the mammalian neonate. In addition to macronutrients like proteins, carbohydrates, and lipids known for their roles in providing substrate and energy, a new class of components has been identified notably microRNA that have signaling roles regulating a large set of biological processes. MicroRNAs, short noncoding RNAs, have been reported to act on the mammary tissues, influencing mammary development and milk component biosynthesis, and evidence is now assembling that they also signal to the infant. The expression profile of these miRNAs can be under nutritional regulation. Their presence in milk and their relative persistency through industrial treatment open new way of investigations to use them as biomarkers of animal health, as well as to evaluate their effects on the health of those consuming them. Due to the role of miRNAs on human health and diseases, their transfer from milk or milk products to infants and adults is being actively researched, though their bioavailability is not known. Research is defining their distribution in the different fractions of milk (such as cells, exosomes, fat globule, or skim milk). Indeed, the unique packaging of miRNAs could be crucial for their action through the intestinal tract. The value of milk miRNAs to diverse aspects of human health is now an emerging field of science.


MicroRNA miRNome Nutritional regulation Expression Bovine Caprine Human Mammary gland Milk Healthy food 

List of Abbreviations


Three prime untranslated region


Acetyl-CoA carboxylase 1


Acyl-CoA synthetase long-chain family member 1


Casein alpha S1


Casein beta


Deoxyribonucleic acid


Estrogen receptor 1


Fatty acid synthase


Glucose transporter 1


Goat mammary epithelial cells


Human epidermal growth factor receptor 2


Mammary epithelial cells


Mammary gland


Microribonucleic acid


Next-generation sequencing


Peroxisome proliferator-activated receptor gamma


RNA-induced silencing complex


Stearoyl-CoA desaturase


Sterol regulatory element-binding protein 1


  1. Alsaweed M, Hartmann PE, Geddes DT, Kakulas F (2015a) MicroRNAs in Breastmilk and the lactating breast: potential immunoprotectors and developmental regulators for the infant and the mother. Int J Environ Res Public Health 12:13981–14020CrossRefGoogle Scholar
  2. Alsaweed M, Hepworth AR, Lefevre C, Hartmann PE et al (2015b) Human milk MicroRNA and Total RNA differ depending on milk fractionation. J Cell Biochem 116:2397–2407CrossRefGoogle Scholar
  3. Alsaweed M, Lai CT, Hartmann PE, Geddes DT, Kakulas F (2016) Human milk cells and lipids conserve numerous known and novel miRNAs, some of which are differentially expressed during lactation. PLoS One 11:e0152610PubMedPubMedCentralGoogle Scholar
  4. Anderson SM, Rudolph MC, Mcmanaman JL, Neville MC (2007) Key stages in mammary gland development – secretory activation in the mammary gland: it's not just about milk protein synthesis! Breast Cancer Res 9:204CrossRefGoogle Scholar
  5. Baier SR, Nguyen C, Xie F, Wood JR, Zempleni J (2014) MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers. J Nutr 144:1495–1500CrossRefGoogle Scholar
  6. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRefGoogle Scholar
  7. Bertoli G, Cava C, Castiglioni I (2015) MicroRNAs: new biomarkers for diagnosis, prognosis, therapy prediction and therapeutic tools for breast cancer. Theranostics 5:1122–1143CrossRefGoogle Scholar
  8. Bian Y, Lei Y, Wang C, Wang J et al (2015) Epigenetic regulation of miR-29s affects the lactation activity of dairy cow mammary epithelial cells. J Cell Physiol 230:2152–2163CrossRefGoogle Scholar
  9. Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10:1957–1966CrossRefGoogle Scholar
  10. Chen X, Gao C, Li H, Huang L et al (2010) Identification and characterization of microRNAs in raw milk during different periods of lactation, commercial fluid, and powdered milk products. Cell Res 20:1128–1137CrossRefGoogle Scholar
  11. Chichlowski M, German JB, Lebrilla CB, Mills DA (2011) The influence of milk oligosaccharides on microbiota of infants: opportunities for formulas. Annu Rev Food Sci Technol 2:331–351CrossRefGoogle Scholar
  12. Cui W, Li Q, Feng L, Ding W (2011) MiR-126-3p regulates progesterone receptors and involves development and lactation of mouse mammary gland. Mol Cell Biochem 355:17–25CrossRefGoogle Scholar
  13. Galio L, Droineau S, Yeboah P, Boudiaf H et al (2013) MicroRNA in the ovine mammary gland during early pregnancy: spatial and temporal expression of miR-21, miR-205, and miR-200. Physiol Genomics 45:151–161CrossRefGoogle Scholar
  14. Gao Y, Cai Q, Huang Y, Li S et al (2016) MicroRNA-21 as a potential diagnostic biomarker for breast cancer patients: a pooled analysis of individual studies. Oncotarget 7:34498–34506PubMedPubMedCentralGoogle Scholar
  15. German JB, Dillard CJ (2010) Saturated fats: a perspective from lactation and milk composition. Lipids 45:915–923CrossRefGoogle Scholar
  16. Givens DI (2010) Milk and meat in our diet: good or bad for health? Animal 4:1941–1952CrossRefGoogle Scholar
  17. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ (2008) miRBase: tools for microRNA genomics. Nucleic Acids Res 36:D154–D158CrossRefGoogle Scholar
  18. Gu Z, Eleswarapu S, Jiang H (2007) Identification and characterization of microRNAs from the bovine adipose tissue and mammary gland. FEBS Lett 581:981–988CrossRefGoogle Scholar
  19. Han J, Lee Y, Yeom KH, Kim YK et al (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–3027CrossRefGoogle Scholar
  20. Howard KM, Jati Kusuma R, Baier SR, Friemel T et al (2015) Loss of miRNAs during processing and storage of cow’s (Bos taurus) milk. J Agric Food Chem 63:588–592CrossRefGoogle Scholar
  21. Humphreys KJ, Mckinnon RA, Michael MZ (2014) miR-18a inhibits CDC42 and plays a tumour suppressor role in colorectal cancer cells. PLoS One 9:e112288CrossRefGoogle Scholar
  22. Ibarra I, Erlich Y, Muthuswamy SK, Sachidanandam R, Hannon GJ (2007) A role for microRNAs in maintenance of mouse mammary epithelial progenitor cells. Genes Dev 21:3238–3243CrossRefGoogle Scholar
  23. Izumi H, Tsuda M, Sato Y, Kosaka N et al (2015) Bovine milk exosomes contain microRNA and mRNA and are taken up by human macrophages. J Dairy Sci 98:2920–2933CrossRefGoogle Scholar
  24. Jahagirdar D, Purohit S, Jain A, Sharma NK (2016) Export of microRNAs: a bridge between breast carcinoma and their neighboring cells. Front Oncol 6:147CrossRefGoogle Scholar
  25. Ji Z, Wang G, Xie Z, Zhang C, Wang J (2012) Identification and characterization of microRNA in the dairy goat (Capra hircus) mammary gland by Solexa deep-sequencing technology. Mol Biol Rep 39(10):9361–71CrossRefGoogle Scholar
  26. Khoshnaw SM, Rakha EA, Abdel-fatah TM, Nolan CC et al (2012) Loss of dicer expression is associated with breast cancer progression and recurrence. Breast Cancer Res Treat 135:403–413CrossRefGoogle Scholar
  27. Khoshnaw SM, Rakha EA, Abdel-fatah T, Nolan CC et al (2013) The microRNA maturation regulator Drosha is an independent predictor of outcome in breast cancer patients. Breast Cancer Res Treat 137:139–153CrossRefGoogle Scholar
  28. Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139CrossRefGoogle Scholar
  29. Kosaka N, Izumi H, Sekine K, Ochiya T (2010) microRNA as a new immune-regulatory agent in breast milk. Silence 1:7–7CrossRefGoogle Scholar
  30. Koutsaki M, Spandidos DA, Zaravinos A (2014) Epithelial-mesenchymal transition-associated miRNAs in ovarian carcinoma, with highlight on the miR-200 family: prognostic value and prospective role in ovarian cancer therapeutics. Cancer Lett 351:173–181CrossRefGoogle Scholar
  31. Lago-Novais D, Pawlowski K, Pires J, Mobuchon L, et al (2016) Milk fat globules as a source of mammary microRNA. In: 2016 ADSA/ASAS Joint Annual Meeting. p 401. Google Scholar
  32. Laubier J, Castille J, Le Guillou S, Le Provost F (2015) No effect of an elevated miR-30b level in mouse milk on its level in pup tissues. RNA Biol 12:26–29CrossRefGoogle Scholar
  33. Le Guillou S, Sdassi N, Laubier J, Passet B et al (2012) Overexpression of miR-30b in the developing mouse mammary gland causes a lactation defect and delays involution. PLoS One 7:e45727CrossRefGoogle Scholar
  34. Le Guillou S, Marthey S, Laloe D, Laubier J et al (2014) Characterisation and comparison of lactating mouse and bovine mammary gland miRNomes. PLoS One 9:e91938CrossRefGoogle Scholar
  35. Lee Y, Jeon K, Lee JT, Kim S, Kim VN (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 21:4663–4670CrossRefGoogle Scholar
  36. Li HM, Wang CM, Li QZ, Gao XJ (2012a) MiR-15a decreases bovine mammary epithelial cell viability and lactation and regulates growth hormone receptor expression. Molecules 17:12037–12048CrossRefGoogle Scholar
  37. Li Z, Liu H, Jin X, Lo L, Liu J (2012b) Expression profiles of microRNAs from lactating and non-lactating bovine mammary glands and identification of miRNA related to lactation. BMC Genomics 13:731CrossRefGoogle Scholar
  38. Li R, Dudemaine PL, Zhao X, Lei C, Ibeagha-awemu EM (2016) Comparative analysis of the miRNome of bovine milk fat, whey and cells. PLoS One 11:e0154129CrossRefGoogle Scholar
  39. Lian S, Guo JR, Nan XM, Ma L et al (2016) MicroRNA Bta-miR-181a regulates the biosynthesis of bovine milk fat by targeting ACSL1. J Dairy Sci 99:3916–3924CrossRefGoogle Scholar
  40. Lin X, Luo J, Zhang L, Wang W, Gou D (2013a) MiR-103 controls milk fat accumulation in goat (Capra Hircus) mammary gland during lactation. PLoS One 8:e79258CrossRefGoogle Scholar
  41. Lin XZ, Luo J, Zhang LP, Wang W et al (2013b) MiR-27a suppresses triglyceride accumulation and affects gene mRNA expression associated with fat metabolism in dairy goat mammary gland epithelial cells. Gene 521:15–23CrossRefGoogle Scholar
  42. Lin X, Zhan JK, Wang YJ, Tan P et al (2016) Function, role, and clinical application of MicroRNAs in vascular aging. Biomed Res Int 2016:6021394PubMedPubMedCentralGoogle Scholar
  43. Malcomson FC, Willis ND, McCallum I, Xie L et al (2017) Non-digestible carbohydrates supplementation increases miR-32 expression in the healthy human colorectal epithelium: a randomized controlled trial. Mol Carcinog.
  44. Marques-Rocha JL, Milagro FI, Mansego ML, Zulet MA et al (2016) Expression of inflammation-related miRNAs in white blood cells from subjects with metabolic syndrome after 8 wk of following a Mediterranean diet-based weight loss program. Nutrition 32:48–55CrossRefGoogle Scholar
  45. Martinez I, Cazalla D, Almstead LL, Steitz JA, Dimaio D (2011) miR-29 and miR-30 regulate B-Myb expression during cellular senescence. Proc Natl Acad Sci USA 108:522–527CrossRefGoogle Scholar
  46. Mercken EM, Majounie E, Ding J, Guo et al (2013) Age-associated miRNA alterations in skeletal muscle from rhesus monkeys reversed by caloric restriction. Aging (Albany NY) 5:692–703CrossRefGoogle Scholar
  47. Milenkovic D, Deval C, Gouranton E, Landrier JF et al (2012) Modulation of miRNA expression by dietary polyphenols in apoE deficient mice: a new mechanism of the action of polyphenols. PLoS One 7:e29837CrossRefGoogle Scholar
  48. Milenkovic D, Jude B, Morand C (2013) miRNA as molecular target of polyphenols underlying their biological effects. Free Radic Biol Med 64:40–51CrossRefGoogle Scholar
  49. Mobuchon L, Marthey S, Boussaha M, Le Guillou S et al (2015a) Annotation of the goat genome using next generation sequencing of microRNA expressed by the lactating mammary gland: comparison of three approaches. BMC Genomics 16:285CrossRefGoogle Scholar
  50. Mobuchon L, Marthey S, Le Guillou S, Laloe D et al (2015b) Food deprivation affects the miRNome in the lactating goat mammary gland. PLoS One 10:e0140111CrossRefGoogle Scholar
  51. Mobuchon L, Le Guillou S, Marthey S, Laubier J et al (2017) Sunflower oil supplementation affects the expression of miR-20a-5p and miR-142-5p in the lactating bovine mammary gland. PLoS One. in pressGoogle Scholar
  52. Munch EM, Harris RA, Mohammad M, Benham AL et al (2013) Transcriptome profiling of microRNA by next-gen deep sequencing reveals known and novel miRNA species in the lipid fraction of human breast milk. PLoS One 8:e50564CrossRefGoogle Scholar
  53. Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T et al (2010) MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328:1566–1569CrossRefGoogle Scholar
  54. Nassar FJ, Nasr R, Talhouk R (2016) MicroRNAs as biomarkers for early breast cancer diagnosis, prognosis and therapy prediction. Pharmacol Ther 172:34–49CrossRefGoogle Scholar
  55. Nouraee N, Mowla SJ (2015) miRNA therapeutics in cardiovascular diseases: promises and problems. Front Genet 6:232CrossRefGoogle Scholar
  56. Ollier S, Robert-Granie C, Bernard L, Chilliard Y, Leroux C (2007) Mammary transcriptome analysis of food-deprived lactating goats highlights genes involved in milk secretion and programmed cell death. J Nutr 137:560–567CrossRefGoogle Scholar
  57. Orom UA, Lim MK, Savage JE, Jin L et al (2012) MicroRNA-203 regulates caveolin-1 in breast tissue during caloric restriction. Cell Cycle 11:1291–1295CrossRefGoogle Scholar
  58. Pando R, Even-Zohar N, Shtaif B, Edry L et al (2012) MicroRNAs in the growth plate are responsive to nutritional cues: association between miR-140 and SIRT1. J Nutr Biochem 23:1474–1481CrossRefGoogle Scholar
  59. Paul S, Lakatos P, Hartmann A, Schneider-Stock R, Vera J (2017) Identification of miRNA-mRNA modules in colorectal cancer using rough hypercuboid based supervised clustering. Sci Rep 7:42809CrossRefGoogle Scholar
  60. Rana TM (2007) Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 8:23–36CrossRefGoogle Scholar
  61. Sayed D, Abdellatif M (2011) Micrornas in development and disease. Physiol Rev 91:827–887CrossRefGoogle Scholar
  62. Sun J, Aswath K, Schroeder SG, Lippolis JD et al (2015) MicroRNA expression profiles of bovine milk exosomes in response to Staphylococcus aureus infection. BMC Geno 16;16:806Google Scholar
  63. Title AC, Denzler R, Stoffel M (2015) Uptake and function studies of maternal milk-derived MicroRNAs. J Biol Chem 290:23680–23691CrossRefGoogle Scholar
  64. Tome-Carneiro J, Larrosa M, Yanez-Gascon MJ, Davalos A et al (2013) One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol Res 72:69–82CrossRefGoogle Scholar
  65. Wang M, Moisa S, Khan MJ, Wang J et al (2012) MicroRNA expression patterns in the bovine mammary gland are affected by stage of lactation. J Dairy Sci 95:6529–6535CrossRefGoogle Scholar
  66. Wang Z, Hou X, Qu B, Wang J et al (2014) Pten regulates development and lactation in the mammary glands of dairy cows. PLoS One 9:e102118CrossRefGoogle Scholar
  67. Wang H, Luo J, Chen Z, Cao WT et al (2015) MicroRNA-24 can control triacylglycerol synthesis in goat mammary epithelial cells by targeting the fatty acid synthase gene. J Dairy Sci 98:9001–9014CrossRefGoogle Scholar
  68. Wang H, Luo J, Zhang T, TIAN H et al (2016) MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting the INSIG1 gene. RNA Biol 13:500–510CrossRefGoogle Scholar
  69. Wicik Z, Gajewska M, Majewska A, Walkiewicz D et al (2016) Characterization of microRNA profile in mammary tissue of dairy and beef breed heifers. J Anim Breed Genet 133(1):31–42CrossRefGoogle Scholar
  70. Xi Y, Jiang X, Li R, Chen M et al (2016) The levels of human milk microRNAs and their association with maternal weight characteristics. Eur J Clin Nutr 70:445–449CrossRefGoogle Scholar
  71. Zeljic K, Supic G, Magic Z (2017) New insights into vitamin D anticancer properties: focus on miRNA modulation. Mol Genet Genomics 292:511–524CrossRefGoogle Scholar
  72. Zempleni J, Baier SR, Howard KM, Cui J (2015) Gene regulation by dietary microRNAs. Can J Physiol Pharmacol 93:1097–1102CrossRefGoogle Scholar
  73. Zempleni J, Aguilar-Lozano A, Sadri M, Sukreet S et al (2017) Biological activities of extracellular vesicles and their cargos from bovine and human milk in humans and implications for infants. J Nutr 147:3–10CrossRefGoogle Scholar
  74. Zhang L, Hou D, Chen X, Li D et al (2012) Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res 22:107–126CrossRefGoogle Scholar
  75. Zhou Q, Li M, Wang X, Li Q et al (2012) Immune-related microRNAs are abundant in breast milk exosomes. Int J Biol Sci 8:118–123CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Christine Leroux
    • 1
    • 2
    Email author
  • Dragan Milenkovic
    • 3
    • 4
  • Lenha Mobuchon
    • 1
  • Sandrine Le Guillou
    • 5
  • Yannick Faulconnier
    • 1
  • Bruce German
    • 2
  • Fabienne Le Provost
    • 5
  1. 1.Herbivore Research Unit -Biomarkers TeamFrench Institut of Agricultural Research (INRA)St Genès-ChampanelleFrance
  2. 2.Department of Food Science and TechnologyUniversity of California DavisDavisUSA
  3. 3.School of Medicine, Division of Cardiovascular MedicineUniversity of California DavisDavisUSA
  4. 4.Department of Human NutritionFrench Institut of Agricultural Research (INRA)St Genès-ChampanelleFrance
  5. 5.Génétique Animale et Biologie IntégrativeFrench Institut of Agricultural Research (INRA)Jouy-en-JosasFrance

Personalised recommendations