Hostname: page-component-8448b6f56d-jr42d Total loading time: 0 Render date: 2024-04-18T21:58:17.648Z Has data issue: false hasContentIssue false
  • English
  • Français

The epigenetic role of breastfeeding in mammary differentiation

Published online by Cambridge University Press:  07 October 2020

Flavia E. Santiano ,
Fiorella Campo Verde Arboccó ,
Flavia A. Bruna ,
Leila E. Zyla ,
Corina V. Sasso ,
Silvina Gómez ,
Virginia Pistone-Creydt ,
Constanza M. López-Fontana  and
Rubén W. Carón Open the ORCID record for Rubén W. Carón [Opens in a new window]
Flavia E. Santiano
Affiliation:
Laboratory of Hormones and Cancer Biology, Institute of Medicine and Experimental Biology of Cuyo, IMBECU, CONICET UNCuyo, Mendoza, Argentina
Fiorella Campo Verde Arboccó
Affiliation:
Laboratory of Hormones and Cancer Biology, Institute of Medicine and Experimental Biology of Cuyo, IMBECU, CONICET UNCuyo, Mendoza, Argentina Physiology Department, School of Medicine, University of Mendoza, Mendoza, Argentina
Flavia A. Bruna
Affiliation:
Laboratory of Hormones and Cancer Biology, Institute of Medicine and Experimental Biology of Cuyo, IMBECU, CONICET UNCuyo, Mendoza, Argentina
Leila E. Zyla
Affiliation:
Laboratory of Hormones and Cancer Biology, Institute of Medicine and Experimental Biology of Cuyo, IMBECU, CONICET UNCuyo, Mendoza, Argentina Physiology Department, School of Medicine, University of Mendoza, Mendoza, Argentina
Corina V. Sasso
Affiliation:
Laboratory of Hormones and Cancer Biology, Institute of Medicine and Experimental Biology of Cuyo, IMBECU, CONICET UNCuyo, Mendoza, Argentina
Silvina Gómez
Affiliation:
Laboratory of Hormones and Cancer Biology, Institute of Medicine and Experimental Biology of Cuyo, IMBECU, CONICET UNCuyo, Mendoza, Argentina
Virginia Pistone-Creydt
Affiliation:
Laboratory of Hormones and Cancer Biology, Institute of Medicine and Experimental Biology of Cuyo, IMBECU, CONICET UNCuyo, Mendoza, Argentina
Constanza M. López-Fontana
Affiliation:
Laboratory of Hormones and Cancer Biology, Institute of Medicine and Experimental Biology of Cuyo, IMBECU, CONICET UNCuyo, Mendoza, Argentina
Rubén W. Carón*
Affiliation:
Laboratory of Hormones and Cancer Biology, Institute of Medicine and Experimental Biology of Cuyo, IMBECU, CONICET UNCuyo, Mendoza, Argentina
*
Address for correspondence: Rubén Walter Carón, Laboratorio de Hormonas y Biología del Cáncer, IMBECU, CONICET, CCT-Mendoza. Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina. Email: rcaron@mendoza-conicet.gob.ar
Get access Rights & Permissions [Opens in a new window]

Abstract

Maternal milk consumption can cause changes in the mammary epithelium of the offspring that result in the expression of molecules involved in the induction of differentiation, reducing the risk of developing mammary cancer later in life. We previously showed that animals that maintained a higher intake of maternal milk had a lower incidence of mammary cancer. In the present study, we evaluated one of the possible mechanisms by which the consumption of maternal milk could modify the susceptibility to mammary carcinogenesis. We used Sprague Dawley rats reared in litters of 3 (L3), 8 (L8), or 12 (L12) pups per mother in order to generate a differential consumption of milk. Whole mounts of mammary glands were performed to analyze the changes in morphology. Using real-time polymerase chain reaction (PCR), we analyzed the expression of mammary Pinc, Tbx3, Stat6, and Gata3 genes. We use the real-time methylation-specific polymerase chain reaction method to assess the methylation status of Stat6 and Gata3 CpG sites. Our findings show an increase in the size of the epithelial tree and a smaller number of ducts called terminal end buds in L3 vs. L12. We observed an increased expression of mRNA of Stat6, Gata3, Tbx3, and a lower expression of Pinc in L3 with respect to L12. Stat6 and Gata3 are more methylated in the CpG islands of the promoter analyzed in L12 vs. L3. In conclusion, the increased consumption of maternal milk during the postnatal stage generates epigenetic and morphological changes associated with the differentiation of the mammary gland.

Keywords

Postnataldevelopmentlactationmammary glandTEBs
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 12 , Issue 4 , August 2021 , pp. 578 - 586
Check for updates
Copyright
© The Author(s), 2020. Published by Cambridge University Press in association with International Society for Developmental Origins of Health and Disease

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Lillycrop, KA, Burdge, GC. Breast cancer and the importance of early life nutrition. Cancer Treat Res. 2014; 159, 269–285. https://doi.org/10.1007/978-3-642-38007-5_16.CrossRefGoogle ScholarPubMed
Robillard, JE, Segar, JL. Influence of early life events on health and diseases. Trans Am Clin Climatol Assoc. 2006; 117, 313–320.Google ScholarPubMed
Gluckman, PD, Hanson, MA, Cooper, C, Thornburg, KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008; 359(1), 61. https://doi.org/10.1056/NEJMra0708473.CrossRefGoogle ScholarPubMed
Gentner, MB, Leppert, MLO. Environmental influences on health and development: nutrition, substance exposure, and adverse childhood experiences. Dev Med Child Neurol. 2019; 61(9), 1008–1014. https://doi.org/10.1111/dmcn.14149.CrossRefGoogle ScholarPubMed
Ballard, O, Morrow, AL. Human milk composition: nutrients and bioactive factors. Pediatr Clin North Am. 2013; 60(1), 49–74. https://doi.org/10.1016/j.pcl.2012.10.002.CrossRefGoogle ScholarPubMed
Iyengar, SR, Walker, WA. Immune factors in breast milk and the development of atopic disease. J Pediatr Gastroenterol Nutr. 2012; 55(6), 641–647. https://doi.org/10.1097/MPG.0b013e3182617a9d.CrossRefGoogle ScholarPubMed
Melnik, BC, Schmitz, G. Milk’s role as an epigenetic regulator in health and disease. Diseases. 2017; 5(1), 12. https://doi.org/10.3390/diseases5010012.CrossRefGoogle ScholarPubMed
Melnik, BC, Kakulas, F, Geddes, DT, et al. Milk miRNAs: simple nutrients or systemic functional regulators? Nutr Metab. 2016; 13, 42. https://doi.org/10.1186/s12986-016-0101-2.CrossRefGoogle ScholarPubMed
Melnik, BC, John, SM, Schmitz, G. Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth. Nutr J. 2013; 12(1), 103. https://doi.org/10.1186/1475-2891-12-103.CrossRefGoogle Scholar
Verduci, E, Banderali, G, Barberi, S, et al. Epigenetic effects of human breast milk. Nutrients. 2014; 6(4), 1711–1724. https://doi.org/10.3390/nu6041711.CrossRefGoogle ScholarPubMed
Hartwig, FP, De Mola, CL, Davies, NM, Victora, CG, Relton, CL. Breastfeeding effects on DNA methylation in the offspring: a systematic literature review. PLoS One. 2017; 12(3), e0173070. https://doi.org/10.1371/journal.pone.0173070.CrossRefGoogle ScholarPubMed
Cutfield, WS, Hofman, PL, Mitchell, M, Morison, IM. Could epigenetics play a role in the developmental origins of health and disease? Pediatr Res. 2007; 61(5 Pt 2), 68R–75R. https://doi.org/10.1203/pdr.0b013e318045764c.CrossRefGoogle ScholarPubMed
Liotto, N, Miozzo, M, Gianni, ML, et al. Early nutrition: the role of genetics and epigenetics. Pediatr Med Chir. 2009; 31(2), 65–71.Google ScholarPubMed
Tammen, SA, Friso, S, Choi, S-W. Epigenetics: the link between nature and nurture. Mol Aspects Med. 2013; 34(4), 753–764. https://doi.org/10.1016/j.mam.2012.07.018.CrossRefGoogle ScholarPubMed
Waterland, RA, Michels, KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr. 2007; 27, 363–388. https://doi.org/10.1146/annurev.nutr.27.061406.093705.CrossRefGoogle ScholarPubMed
Danaei, G, Vander Hoorn, S, Lopez, AD, Murray, CJL, Ezzati, M. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet. 2005; 366(9499), 1784–1793. https://doi.org/10.1016/S0140-6736(05)67725-2.CrossRefGoogle ScholarPubMed
Martin, RM, Middleton, N, Gunnell, D, Owen, CG, Smith, GD. Breast-feeding and cancer: the Boyd Orr cohort and a systematic review with meta-analysis. J Natl Cancer Inst. 2005; 97(19), 1446–1457. https://doi.org/10.1093/jnci/dji291.CrossRefGoogle Scholar
Geddes, DT. Inside the lactating breast: the latest anatomy research. J Midwifery Womens Health. 2007; 52(6), 556–563. https://doi.org/10.1016/j.jmwh.2007.05.004.CrossRefGoogle ScholarPubMed
Russo, J, Russo, IH. Development of the human breast. Maturitas. 2004; 49, 2–15. https://doi.org/10.1016/j.maturitas.2004.04.011.CrossRefGoogle ScholarPubMed
Javed, A, Lteif, A. Development of the human breast. Semin Plast Surg. 2013; 27(1), 5–12. https://doi.org/10.1055/s-0033-1343989.Google ScholarPubMed
Naccarato, AG, Viacava, P, Vignati, S, et al. Bio-morphological events in the development of the human female mammary gland from fetal age to puberty. Virchows Arch. 2000; 436(5), 431–438. https://doi.org/10.1007/s004280050470.CrossRefGoogle ScholarPubMed
Howard, BA, Gusterson, BA. Human breast development. J Mammary Gland Biol Neoplasia. 2000; 5(2), 119–137.CrossRefGoogle ScholarPubMed
Russo, J, Gusterson, BA, Rogers, AE, Russo, IH, Wellings, SR, van Zwieten, MJ. Comparative study of human and rat mammary tumorigenesis. Lab Invest. 1990; 62(3), 244–278.Google ScholarPubMed
Russo, J, Russo, IH. Biological and molecular bases of mammary carcinogenesis. Lab Invest. 1987; 57(2), 112–137.Google ScholarPubMed
Figueroa, JD, Pfeiffer, RM, Patel, DA, et al. Terminal duct lobular unit involution of the normal breast: implications for breast cancer etiology. J Natl Cancer Inst. 2014; 106(10), dju286. https://doi.org/10.1093/jnci/dju286.CrossRefGoogle ScholarPubMed
Russo, J, Russo, IH. Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis. Cancer Res. 1980; 40(8), 2677–2687.Google ScholarPubMed
Haricharan, S, Li, Y. STAT signaling in mammary gland differentiation, cell survival and tumorigenesis. Mol Cell Endocrinol. 2014; 382(1), 560–569. https://doi.org/10.1016/j.mce.2013.03.014.CrossRefGoogle ScholarPubMed
Khaled, WT, Read, EKC, Nicholson, SE, et al. The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development. Development. 2007; 134(15), 2739–2750. https://doi.org/10.1242/dev.003194.CrossRefGoogle ScholarPubMed
Kouros-Mehr, H, Slorach, EM, Sternlicht, MD, Werb, Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell. 2006; 127(5), 1041–1055. https://doi.org/10.1016/j.cell.2006.09.048.CrossRefGoogle ScholarPubMed
Shore, AN, Kabotyanski, EB, Roarty, K, et al. Pregnancy-induced noncoding RNA (PINC) associates with polycomb repressive complex 2 and regulates mammary epithelial differentiation. PLoS Genet. 2012; 8(7), e1002840. https://doi.org/10.1371/journal.pgen.1002840.CrossRefGoogle ScholarPubMed
Rowley, M, Grothey, E, Couch, FJ. The role of Tbx2 and Tbx3 in mammary development and tumorigenesis. J Mammary Gland Biol Neoplasia. 2004; 9(2), 109–118. https://doi.org/10.1023/B:JOMG.0000037156.64331.3f.CrossRefGoogle ScholarPubMed
Santiano, FE, Zyla, LE, Campo Verde-Arboccó, F, et al. High maternal milk intake in the postnatal life reduces the incidence of breast cancer during adulthood in rats. J Dev Orig Health Dis. 2019; 10(4), 479–487. https://doi.org/10.1017/s2040174418001071.CrossRefGoogle ScholarPubMed
Barbazanges, A, Vallée, M, Mayo, W, et al. Early and later adoptions have different long-term effects on male rat offspring. J Neurosci. 1996; 16(23), 7783–7790. https://doi.org/10.1523/jneurosci.16-23-07783.1996.CrossRefGoogle ScholarPubMed
de Assis, S, Warri, A, Cruz, MI, Hilakivi-Clarke, L. Changes in mammary gland morphology and breast cancer risk in rats. J Vis Exp. 2010;(44), 2260. https://doi.org/10.3791/2260.CrossRefGoogle Scholar
Pfaffl, MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29(9), 45e. https://doi.org/10.1093/nar/29.9.e45.CrossRefGoogle ScholarPubMed
Schindelin, J, Arganda-Carreras, I, Frise, E, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012; 9(7), 676–682. https://doi.org/10.1038/nmeth.2019.CrossRefGoogle ScholarPubMed
Danquah, I, Addo, J, Boateng, D, et al. Early-life factors are associated with waist circumference and type 2 diabetes among Ghanaian adults: the RODAM study. Sci Rep. 2019; 9(1), 10848. https://doi.org/10.1038/s41598-019-47169-6.CrossRefGoogle ScholarPubMed
Heidari-Beni, M. Early life nutrition and non communicable disease. Adv Exp Med Biol. 2019; 1121, 33–40. Springer New York LLC. https://doi.org/10.1007/978-3-030-10616-4_4.CrossRefGoogle ScholarPubMed
Greco, EA, Lenzi, A, Migliaccio, S, Gessani, S. Epigenetic modifications induced by nutrients in early life phases: gender differences in metabolic alteration in adulthood. Front Genet. 2019; 10, 795. https://doi.org/10.3389/fgene.2019.00795.CrossRefGoogle ScholarPubMed
Habbout, A, Li, N, Rochette, L, Vergely, C. Postnatal overfeeding in rodents by litter size reduction induces major short- and long-term pathophysiological consequences. J Nutr. 2013; 143(5), 553–562. https://doi.org/10.3945/jn.112.172825.CrossRefGoogle Scholar
Hilakivi-Clarke, L, Shajahan, A, Yu, B, de Assis, S. Differentiation of mammary gland as a mechanism to reduce breast cancer risk. J Nutr. 2006; 136(10), 2697S–2699S. https://doi.org/10.1093/jn/136.10.2697s.CrossRefGoogle ScholarPubMed
Shimoda, K, van Deursent, J, Sangster, MY, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted State6 gene. Nature. 1996; 380(6575), 630–633. https://doi.org/10.1038/380630a0.CrossRefGoogle ScholarPubMed
Takeda, K, Tanaka, T, Shi, W, et al. Essential role of Stat6 in IL-4 signalling. Nature. 1996; 380(6575), 627–630. https://doi.org/10.1038/380627a0.CrossRefGoogle ScholarPubMed
Asselin-Labat, ML, Sutherland, KD, Barker, H, et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol. 2007; 9(2), 201–209. https://doi.org/10.1038/ncb1530.CrossRefGoogle ScholarPubMed
Newell-Price, J, Clark, AJL, King, P. DNA methylation and silencing of gene expression. Trends Endocrinol Metab. 2000; 11(4), 142–148. https://doi.org/10.1016/S1043-2760(00)00248-4.CrossRefGoogle ScholarPubMed
Curradi, M, Izzo, A, Badaracco, G, Landsberger, N. Molecular mechanisms of gene silencing mediated by DNA methylation. Mol Cell Biol. 2002; 22(9), 3157–3173. https://doi.org/10.1128/mcb.22.9.3157-3173.2002.CrossRefGoogle ScholarPubMed
Thuy, LHA, Thuan, LD, Phuong, TK. DNA Hypermethylation in Breast Cancer. In: Breast Cancer - From Biology to Medicine, Phuc Van Pham, IntechOpen; 2017; https://doi.org/10.5772/66900.CrossRefGoogle Scholar