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Pubertal exposure to high fat diet causes mouse strain-dependent alterations in mammary gland development and estrogen responsiveness

International Journal of Obesity volume 34, pages 1415–1426 (2010)Cite this article

Subjects

Abstract

Objective:

Increased adolescent obesity rates in the United States are a significant public health concern. Obesity or increased adiposity during puberty in girls, an important period of breast development and a window of exposure sensitivity, may influence breast development and cancer risk. The purpose of this study was to investigate the impact of a high fat diet (HFD) on mammary gland development in obesity-susceptible C57BL/6 and obesity-resistant BALB/c mice.

Design:

Pubertal or adult C57BL/6 and BALB/c mice were fed an HFD or control diet (CD) from 3 to 7 weeks of age or from 10 to 14 weeks of age, respectively. The effects of HFD diet on body weight, adiposity, mammary gland development, and mammary gland response to estrogen were evaluated.

Results:

Pubertal C57BL/6 mice fed the HFD had a significant increase in body weight and adiposity, and this was accompanied by stunted mammary duct elongation and reduced mammary epithelial cell proliferation. Ovariectomy and estrogen (17-β-estradiol, E) treatment of pubertal HFD-fed C57BL/6 mice showed decreased mammary gland stimulation by E. Amphiregulin, a downstream mediator of pubertal E action, was reduced in mammary glands of HFD-fed C57BL/6 mice. Weight loss and reduced adiposity initiated by switching C57BL/6 mice from HFD to CD restored ductal elongation. Pubertal BALB/c mice fed the HFD did not exhibit a significant increase in body weight or adiposity; HFD caused increased mammary epithelial cell proliferation and had no effect on response to E. HFD had no effect on body weight or the mammary glands of adult mice.

Conclusions:

HFD during puberty had a profound strain-specific effect on murine mammary gland development. Obesity and increased adiposity were associated with reduced responsiveness to estrogen and stunted ductal growth. Importantly, the effect of diet and adiposity on the mammary gland was specific to the pubertal period of development.

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References

  1. Rosenfield RL, Lipton RB, Drum ML . Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index. Pediatrics 2009; 123: 84–88.

    Article  Google Scholar 

  2. Marchand L, Kolonel LN, Earle ME, Mi M-P . Body size at different periods of life and breast cancer risk. Am J Epidemiol 1988; 128: 137–152.

    Article  Google Scholar 

  3. Magnusson C, Baron J, Persson I, Wolk A, Bergstrom R, Trichopoulos D et al. Body size in different periods of life and breast cancer risk in post-menopausal women. Int J Cancer 1998; 76: 29–34.

    Article  CAS  Google Scholar 

  4. Berkey CS, Frazier AL, Gardner JD, Colditz GA . Adolescence and breast carcinoma risk. Cancer 1999; 85: 2400–2409.

    Article  CAS  Google Scholar 

  5. Hilakivi-Clarke L, Forsen T, Eriksson JG, Luoto R, Tuomilehto J, Osmond C et al. Tallness and overweight during childhood have opposing effects on breast cancer risk. Br J Cancer 2001; 85: 1680–1684.

    Article  CAS  Google Scholar 

  6. Ahlgren M, Melbye M, Wohlfahrt J, Sorensen TI . Growth patterns and the risk of breast cancer in women. N Engl J Med 2004; 351: 1619–1626.

    Article  CAS  Google Scholar 

  7. Baer HJ, Colditz GA, Rosner B, Michels KB, Rich-Edwards JW, Hunter DJ et al. Body fatness during childhood and adolescence and incidence of breast cancer in premenopausal women: a prospective cohort study. Breast Cancer Res 2005; 7: R314–R325.

    Article  Google Scholar 

  8. Garland M, Hunter DJ, Colditz GA, Manson JE, Stampfer MJ, Spiegelman D et al. Menstrual cycle characteristics and history of ovulatory infertility in relation to breast cancer risk in a large cohort of US women. Am J Epidemiol 1998; 147: 636–643.

    Article  CAS  Google Scholar 

  9. Titus-Ernstoff L, Longnecker MP, Newcomb PA, Dain B, Greenberg ER, Mittendorf R et al. Menstrual factors in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev 1998; 7: 783–789.

    CAS  PubMed  Google Scholar 

  10. Hannon TS, Rao G, Arslanian SA . Childhood obesity and type 2 diabetes mellitus. Pediatrics 2005; 116: 473–480.

    Article  Google Scholar 

  11. Watson CJ, Khaled WT . Mammary development in the embryo and adult: a journey of morphogenesis and commitment. Development (Cambridge, England) 2008; 135: 995–1003.

    Article  CAS  Google Scholar 

  12. Russo J, Russo IH . Biological and molecular bases of mammary carcinogenesis. Lab Invest 1987; 57: 112–137.

    CAS  PubMed  Google Scholar 

  13. Welsch CW . Relationship between dietary fat and experimental mammary tumorigenesis: a review and critique. Cancer Res 1992; 52: 2040s–2048s.

    CAS  PubMed  Google Scholar 

  14. Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman M . A maternal diet high in n—6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Proc Natl Acad Sci USA 1997; 94: 9372–9377.

    Article  CAS  Google Scholar 

  15. Hilakivi-Clarke L, Cho E, Cabanes A, DeAssis S, Olivo S, Helferich W et al. Dietary modulation of pregnancy estrogen levels and breast cancer risk among female rat offspring. Clin Cancer Res 2002; 8: 3601–3610.

    CAS  PubMed  Google Scholar 

  16. Hilakivi-Clarke L, Stoica A, Raygada M, Martin MB . Consumption of a high-fat diet alters estrogen receptor content, protein kinase C activity, and mammary gland morphology in virgin and pregnant mice and female offspring. Cancer Res 1998; 58: 654–660.

    CAS  PubMed  Google Scholar 

  17. Welsch CW, DeHoog JV, O’Connor DH, Sheffield LG . Influence of dietary fat levels on development and hormone responsiveness of the mouse mammary gland. Cancer Res 1985; 45: 6147–6154.

    CAS  PubMed  Google Scholar 

  18. Welsch CW, O’Connor DH . Influence of the type of dietary fat on developmental growth of the mammary gland in immature and mature female BALB/c mice. Cancer Res 1989; 49: 5999–6007.

    CAS  PubMed  Google Scholar 

  19. Kamikawa A, Ichii O, Yamaji D, Imao T, Suzuki C, Okamatsu-Ogura Y et al. Diet-induced obesity disrupts ductal development in the mammary glands of nonpregnant mice. Dev Dyn 2009; 238: 1092–1099.

    Article  CAS  Google Scholar 

  20. Banerjee M, Wood B, Lin F, Crump L . Organ culture of whole mammary gland of the mouse. Tissue Cult Assoc Manual 1976; 2: 457–462.

    Article  CAS  Google Scholar 

  21. Aupperlee MD, Smith KT, Kariagina A, Haslam SZ . Progesterone receptor isoforms A and B: temporal and spatial differences in expression during murine mammary gland development. Endocrinology 2005; 146: 3577–3588.

    Article  CAS  Google Scholar 

  22. Yang C, Tan YS, Harkema JR, Haslam SZ . Differential effects of peripubertal exposure to perfluorooctanoic acid on mammary gland development in C57Bl/6 and Balb/c mouse strains. Reprod Toxicol 2009; 27: 299–306.

    Article  CAS  Google Scholar 

  23. Aupperlee MD, Haslam SZ . Differential hormonal regulation and function of progesterone receptor isoforms in normal adult mouse mammary gland. Endocrinology 2007; 148: 2290–2300.

    Article  CAS  Google Scholar 

  24. van Dierendonck JH, Wijsman JH, Keijzer R, van de Velde CJ, Cornelisse CJ . Cell-cycle-related staining patterns of anti-proliferating cell nuclear antigen monoclonal antibodies. Comparison with BrdUrd labeling and Ki-67 staining. Am J Pathol 1991; 138: 1165–1172.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Daniel CW, Silberstein GB, Strickland P . Direct action of 17 beta-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. Cancer Res 1987; 47: 6052–6057.

    CAS  PubMed  Google Scholar 

  26. Ciarloni L, Mallepell S, Brisken C . Amphiregulin is an essential mediator of estrogen receptor alpha function in mammary gland development. Proc Natl Acad Sci USA 2007; 104: 5455–5460.

    Article  CAS  Google Scholar 

  27. Aupperlee MD, Drolet AA, Durairaj S, Wang W, Schwartz RC, Haslam SZ . Strain-specific differences in the mechanisms of progesterone regulation of murine mammary gland development. Endocrinology 2009; 150: 1485–1494.

    Article  CAS  Google Scholar 

  28. Surwit RS, Feinglos MN, Rodin J, Sutherland A, Petro AE, Opara EC et al. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metab Clin Exp 1995; 44: 645–651.

    Article  CAS  Google Scholar 

  29. Clee SM, Attie AD . The genetic landscape of type 2 diabetes in mice. Endocr Rev 2007; 28: 48–83.

    Article  CAS  Google Scholar 

  30. Haramizu S, Nagasawa A, Ota N, Hase T, Tokimitsu I, Murase T . Different contribution of muscle and liver lipid metabolism to endurance capacity and obesity susceptibility of mice. J Appl Physiol 2009; 106: 871–879.

    Article  CAS  Google Scholar 

  31. Silberstein GB, Van Horn K, Shyamala G, Daniel CW . Essential role of endogenous estrogen in directly stimulating mammary growth demonstrated by implants containing pure antiestrogens. Endocrinology 1994; 134: 84–90.

    Article  CAS  Google Scholar 

  32. Korach KS, Couse JF, Curtis SW, Washburn TF, Lindzey J, Kimbro KS et al. Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. Recent ProgHorm Res 1996; 51: 159–186; discussion 186-188.

    CAS  Google Scholar 

  33. Eckstein B, Golan R, Shani J . Onset of puberty in the immature female rat induced by 5 -androstane-3,17 -diol. Endocrinology 1973; 92: 941–945.

    Article  CAS  Google Scholar 

  34. Sternlicht MD, Sunnarborg SW . The ADAM17-amphiregulin-EGFR axis in mammary development and cancer. J Mammary Gland Biol Neoplasia 2008; 13: 181–194.

    Article  Google Scholar 

  35. McBryan J, Howlin J, Napoletano S, Martin F . Amphiregulin: role in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 2008; 13: 159–169.

    Article  Google Scholar 

  36. Hu X, Juneja SC, Maihle NJ, Cleary MP . Leptin—a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 2002; 94: 1704–1711.

    Article  CAS  Google Scholar 

  37. Coleman DL, Hummel KP . Studies with the mutation, diabetes, in the mouse. Diabetologia 1967; 3: 238–248.

    Article  CAS  Google Scholar 

  38. Barash IA, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL et al. Leptin is a metabolic signal to the reproductive system. Endocrinology 1996; 137: 3144–3147.

    Article  CAS  Google Scholar 

  39. Silva LF, Etchebarne BE, Nielsen MS, Liesman JS, Kiupel M, VandeHaar MJ . Intramammary infusion of leptin decreases proliferation of mammary epithelial cells in prepubertal heifers. J Dairy Sci 2008; 91: 3034–3044.

    Article  CAS  Google Scholar 

  40. Hadsell DL, Bonnette SG . IGF and insulin action in the mammary gland: lessons from transgenic and knockout models. J Mammary Gland Biol Neoplasia 2000; 5: 19–30.

    Article  CAS  Google Scholar 

  41. Naylor MJ, Ormandy CJ . Mouse strain-specific patterns of mammary epithelial ductal side branching are elicited by stromal factors. Dev Dyn 2002; 225: 100–105.

    Article  CAS  Google Scholar 

  42. Yant Y, Gusterson B, Kamalati T . Induction of strain-specific mouse mammary gland ductal architecture. Breast 1998; 7: 269–272.

    Article  Google Scholar 

  43. Rasouli N, Kern PA . Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab 2008; 93: S64–S73.

    Article  CAS  Google Scholar 

  44. Gouon-Evans V, Rothenberg ME, Pollard JW . Postnatal mammary gland development requires macrophages and eosinophils. Development 2000; 127: 2269–2282.

    CAS  PubMed  Google Scholar 

  45. Wueest S, Rapold RA, Rytka JM, Schoenle EJ, Konrad D . Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice. Diabetologia 2009; 52: 541–546.

    Article  CAS  Google Scholar 

  46. Hinck L, Silberstein GB . Key stages in mammary gland development: the mammary end bud as a motile organ. Breast Cancer Res 2005; 7: 245–251.

    Article  CAS  Google Scholar 

  47. Rausch ME, Weisberg S, Vardhana P, Tortoriello DV . Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (2005) 2008; 32: 451–463.

    Article  CAS  Google Scholar 

  48. Trayhurn P, Wang B, Wood IS . Hypoxia and the endocrine and signalling role of white adipose tissue. Arch Physiol Biochem 2008; 114: 267–276.

    Article  CAS  Google Scholar 

  49. Hilakivi-Clarke L . Nutritional modulation of terminal end buds: its relevance to breast cancer prevention. Curr Cancer Drug Targets 2007; 7: 465–474.

    Article  CAS  Google Scholar 

  50. Oza AM, Boyd NF . Mammographic parenchymal patterns: a marker of breast cancer risk. Epidemiol Rev 1993; 15: 196–208.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors sincerely thank Sarah Woiderski, Sara Hawes, and Christopher D Green for their excellent technical support. This work was supported by the Breast Cancer and the Environment Research Centers Grant U01 ES/CA 012800 from the National Institute of Environment Health Science (NIEHS) and the National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health, and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS or NCI, NIH.

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Authors and Affiliations

  1. Breast Cancer and the Environment Research Center, Michigan State University, East Lansing, MI, USA

    L K Olson, Y Tan, Y Zhao, M D Aupperlee & S Z Haslam

  2. Department of Physiology, Michigan State University, East Lansing, MI, USA

    L K Olson, Y Tan, Y Zhao, M D Aupperlee & S Z Haslam

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  1. L K Olson
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Correspondence to L K Olson.

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Olson, L., Tan, Y., Zhao, Y. et al. Pubertal exposure to high fat diet causes mouse strain-dependent alterations in mammary gland development and estrogen responsiveness. Int J Obes 34, 1415–1426 (2010). https://doi.org/10.1038/ijo.2010.51

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