Skip to main content

Advertisement

SpringerLink
Log in

Psychosocial Stress Exposure Disrupts Mammary Gland Development

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Exposure to psychosocial stressors and ensuing stress physiology have been associated with spontaneous invasive mammary tumors in the Sprague-Dawley rat model of human breast cancer. Mammary gland (MG) development is a time when physiologic and environmental exposures influence breast cancer risk. However, the effect of psychosocial stress exposure on MG development remains unknown. Here, in the first comprehensive longitudinal study of MG development in nulliparous female rats (from puberty through young adulthood; 8–25 wks of age), we quantify the spatial gradient of differentiation within the MG of socially stressed (isolated) and control (grouped) rats. We then demonstrate that social isolation increased stress reactivity to everyday stressors, resulting in downregulation of glucocorticoid receptor (GR) expression in the MG epithelium. Surprisingly, given that chemical carcinogens increase MG cancer risk by preventing normal terminal end bud (TEB) differentiation, chronic isolation stress did not alter TEBs. Instead, isolation blunted MG growth and alveolobular differentiation and reduced epithelial cell proliferation in these structures. Social isolation also enhanced corpora luteal progesterone at all ages but reduced estrogenization only in early adulthood, a pattern that precludes modulated ovarian function as a sufficient mechanism for the effects of isolation on MG development. This longitudinal study of natural variation provides an integrated view of MG development and the importance of increased GR activation in nulliparous ductal growth and alveolobular differentiation. Thus, social isolation and its physiological sequelae disrupt MG growth and differentiation and suggest a contribution of stress exposure during puberty and young adulthood to the previously observed increase in invasive MG cancer observed in chronically socially-isolated adult Sprague-Dawley rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Hermes GL, Delgado B, Tretiakova M, Cavigelli SA, Krausz T, Conzen SD, et al. Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors. Proc Natl Acad Sci U S A. 2009;106(52):22393–8. https://doi.org/10.1073/pnas.0910753106.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Russo J, Mailo D, Hu YF, Balogh G, Sheriff F, Russo IH. Breast differentiation and its implication in cancer prevention. Clin Cancer Res. 2005;11(2 Pt 2):931s–6s.

    CAS  PubMed  Google Scholar 

  3. MacMahon B, Cole P, Lin TM, Lowe CR, Mirra AP, Ravnihar B, et al. Age at first birth and breast cancer risk. Bull World Health Organ. 1970;43(2):209–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Colditz GA, Frazier AL. Models of breast cancer show that risk is set by events of early life: prevention efforts must shift focus. Cancer Epidemiol Biomark Prev. 1995;4(5):567–71.

    CAS  Google Scholar 

  5. Osborne G, Rudel R, Schwarzman M. Evaluating chemical effects on mammary gland development: a critical need in disease prevention. Reprod Toxicol. 2015;54:148–55. https://doi.org/10.1016/j.reprotox.2014.07.077.

    Article  CAS  PubMed  Google Scholar 

  6. Hermes GL, McClintock MK. Isolation and the timing of mammary gland development, gonadarche, and ovarian senescence: implications for mammary tumor burden. Dev Psychobiol. 2008;50(4):353–60. https://doi.org/10.1002/dev.20295.

    Article  PubMed  Google Scholar 

  7. Brisken C. Hormonal control of alveolar development and its implications for breast carcinogenesis. J Mammary Gland Biol Neoplasia. 2002;7(1):39–48.

    Article  Google Scholar 

  8. Hovey RC, Trott JF, Vonderhaar BK. Establishing a framework for the functional mammary gland: from endocrinology to morphology. J Mammary Gland Biol Neoplasia. 2002;7(1):17–38.

    Article  Google Scholar 

  9. Andrechek ER, Mori S, Rempel RE, Chang JT, Nevins JR. Patterns of cell signaling pathway activation that characterize mammary development. Development. 2008;135(14):2403–13.

    Article  CAS  Google Scholar 

  10. Young SL. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity. Reprod BioMed Online. 2013;27(5):497–505. https://doi.org/10.1016/j.rbmo.2013.06.010.

    Article  CAS  PubMed  Google Scholar 

  11. Paine IS, Lewis MT. The terminal end bud: the little engine that could. J Mammary Gland Biol Neoplasia. 2017;22(2):93–108. https://doi.org/10.1007/s10911-017-9372-0.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Frenkel K, Wei L, Wei H. 7,12-dimethylbenz[a]anthracene induces oxidative DNA modification in vivo. Free Radic Biol Med. 1995;19(3):373–80.

    Article  CAS  Google Scholar 

  13. Abba MC, Zhong Y, Lee J, Kil H, Lu Y, Takata Y, et al. DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations. Oncotarget. 2016;7(39):64289–99. https://doi.org/10.18632/oncotarget.11733.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Russo J, Wilgus G, Russo IH. Susceptibility of the mammary gland to carcinogenesis: I Differentiation of the mammary gland as determinant of tumor incidence and type of lesion. Am J Pathol. 1979;96(3):721–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Russo IH, Russo J. Developmental stage of the rat mammary gland as determinant of its susceptibility to 7,12-dimethylbenz[a]anthracene. J Natl Cancer Inst. 1978;61(6):1439–49.

    CAS  PubMed  Google Scholar 

  16. Cavalieri E, Rogan E. Mechanisms of tumor initiation by polycyclic aromatic hydrocarbons. In: Nielson A, editor. PAHs and related compounds. Berlin: Springer; 1978. p. 81–118.

    Google Scholar 

  17. Goodman MT, Cologne JB, Moriwaki H, Vaeth M, Mabuchi K. Risk factors for primary breast cancer in Japan: 8-year follow-up of atomic bomb survivors. Prev Med. 1997;26(1):144–53. https://doi.org/10.1006/pmed.1996.9979.

    Article  CAS  PubMed  Google Scholar 

  18. Bernstein L. Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia. 2002;7(1):3–15.

    Article  Google Scholar 

  19. Sinha DK, Pazik JE, Dao TL. Prevention of mammary carcinogenesis in rats by pregnancy: effect of full-term and interrupted pregnancy. Br J Cancer. 1988;57(4):390–4.

    Article  CAS  Google Scholar 

  20. 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–9S.

    Article  CAS  Google Scholar 

  21. Medina D. Mammary developmental fate and breast cancer risk. Endocr Relat Cancer. 2005;12(3):483–95. https://doi.org/10.1677/erc.1.00804.

    Article  CAS  PubMed  Google Scholar 

  22. D'Cruz CM, Moody SE, Master SR, Hartman JL, Keiper EA, Imielinski MB, et al. Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol. 2002;16(9):2034–51. https://doi.org/10.1210/me.2002-0073.

    Article  CAS  PubMed  Google Scholar 

  23. Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, van Zwieten MJ. Comparative study of human and rat mammary tumorigenesis. Lab Investig. 1990;62(3):244–78.

    CAS  PubMed  Google Scholar 

  24. 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 Pt 1):2677–87.

    CAS  PubMed  Google Scholar 

  25. Russo IH, Russo J. Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect. 1996;104(9):938–67.

    Article  CAS  Google Scholar 

  26. Hovey RC, Coder PS, Wolf JC, Sielken RL Jr, Tisdel MO, Breckenridge CB. Quantitative assessment of mammary gland development in female Long Evans rats following in utero exposure to atrazine. Toxicol Sci. 2011;119(2):380–90. https://doi.org/10.1093/toxsci/kfq337.

    Article  CAS  PubMed  Google Scholar 

  27. Hvid H, Thorup I, Sjogren I, Oleksiewicz MB, Jensen HE. Mammary gland proliferation in female rats: effects of the estrous cycle, pseudo-pregnancy and age. Exp Toxicol Pathol. 2012;64(4):321–32. https://doi.org/10.1016/j.etp.2010.09.005.

    Article  CAS  PubMed  Google Scholar 

  28. Masso-Welch PA, Darcy KM, Stangle-Castor NC, Ip MM. A developmental atlas of rat mammary gland histology. J Mammary Gland Biol Neoplasia. 2000;5(2):165–85.

    Article  CAS  Google Scholar 

  29. Ormerod EJ, Rudland PS. Cellular composition and organization of ductal buds in developing rat mammary glands: evidence for morphological intermediates between epithelial and myoepithelial cells. Am J Anat. 1984;170(4):631–52. https://doi.org/10.1002/aja.1001700408.

    Article  CAS  PubMed  Google Scholar 

  30. Russo IH, Medado J, Russo J. Endocrine influences on the mammary gland. In: Jones TC, Mohr U, Hunt RD, editors. Integument and mammary glands. Berlin: Springer Berlin Heidelberg; 1989. p. 252–66.

    Chapter  Google Scholar 

  31. Schedin P, Mitrenga T, Kaeck M. Estrous cycle regulation of mammary epithelial cell proliferation, differentiation, and death in the Sprague-Dawley rat: a model for investigating the role of estrous cycling in mammary carcinogenesis. J Mammary Gland Biol Neoplasia. 2000;5(2):211–25.

    Article  CAS  Google Scholar 

  32. Sinha YN, Tucker HA. Mammary gland growth of rats between 10 and 100 days of age. Am J Phys. 1966;210(3):601–5. https://doi.org/10.1152/ajplegacy.1966.210.3.601.

    Article  CAS  Google Scholar 

  33. Russo J, Russo IH. Biological and molecular bases of mammary carcinogenesis. Lab Investig. 1987;57(2):112–37.

    CAS  PubMed  Google Scholar 

  34. Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote PA, Clarke CL, et al. Progesterone induces adult mammary stem cell expansion. Nature. 2010;465(7299):803–7. https://doi.org/10.1038/nature09091.

    Article  CAS  PubMed  Google Scholar 

  35. Mathews TJ, Hamilton BE. Mean age of mothers is on the rise: United States, 2000-2014. NCHS Data Brief. 2016;232:1–8.

    Google Scholar 

  36. Astwood EB, Geschickter CF, Rausch EO. Development of the mammary gland of the rat: a study of normal, experimental and pathologic changes and their endocrine relationships. Am J Anat. 1937;61(3):373–405. https://doi.org/10.1002/aja.1000610303.

    Article  CAS  Google Scholar 

  37. Smith TC. The effect of estrogen and progesterone of mammary gland growth in the rat. Endocrinology. 1955;57(1):33–43. https://doi.org/10.1210/endo-57-1-33.

    Article  CAS  PubMed  Google Scholar 

  38. Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A. 2006;103(7):2196–201. https://doi.org/10.1073/pnas.0510974103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Haslam SZ, Shyamala G. Effect of oestradiol on progesterone receptors in normal mammary glands and its relationship with lactation. Biochem J. 1979;182(1):127–31.

    Article  CAS  Google Scholar 

  40. Brisken C, O'Malley B. Hormone action in the mammary gland. Cold Spring Harb Perspect Biol. 2010;2(12):a003178. https://doi.org/10.1101/cshperspect.a003178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Surbey MK. Family composition, stress, and the timing of human menarche. Socioendocrinology of primate reproduction. Monographs in primatology, Vol. 13. New York: Wiley-Liss; 1990. p. 11–32.

    Google Scholar 

  42. Sung S, Simpson JA, Griskevicius V, Kuo SI, Schlomer GL, Belsky J. Secure infant-mother attachment buffers the effect of early-life stress on age of menarche. Psychol Sci. 2016;27(5):667–74. https://doi.org/10.1177/0956797616631958.

    Article  PubMed  Google Scholar 

  43. Fenster L, Waller K, Chen J, Hubbard AE, Windham GC, Elkin E, et al. Psychological stress in the workplace and menstrual function. Am J Epidemiol. 1999;149(2):127–34.

    Article  CAS  Google Scholar 

  44. Yee JR, Cavigelli SA, Delgado B, McClintock MK. Reciprocal affiliation among adolescent rats during a mild group stressor predicts mammary tumors and lifespan. Psychosom Med. 2008;70(9):1050–9. https://doi.org/10.1097/PSY.0b013e31818425fb.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. West DC, Pan D, Tonsing-Carter EY, Hernandez KM, Pierce CF, Styke SC, et al. GR and ER coactivation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome. Mol Cancer Res. 2016;14(8):707–19. https://doi.org/10.1158/1541-7786.MCR-15-0433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang F, Ma Q, Liu Z, Li W, Tan Y, Jin C, et al. Glucocorticoid receptor: MegaTrans switching mediates the repression of an ERalpha-regulated transcriptional program. Mol Cell. 2017;66(3):321–31 e6. https://doi.org/10.1016/j.molcel.2017.03.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhu Z, Jiang W, Thompson HJ. Effect of corticosterone administration on mammary gland development and p27 expression and their relationship to the effects of energy restriction on mammary carcinogenesis. Carcinogenesis. 1998;19(12):2101–6.

    Article  CAS  Google Scholar 

  48. Hankin BL, Badanes LS, Abela JR, Watamura SE. Hypothalamic-pituitary-adrenal axis dysregulation in dysphoric children and adolescents: cortisol reactivity to psychosocial stress from preschool through middle adolescence. Biol Psychiatry. 2010;68(5):484–90. https://doi.org/10.1016/j.biopsych.2010.04.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Decker SA. Salivary cortisol and social status among Dominican men. Horm Behav. 2000;38(1):29–38. https://doi.org/10.1006/hbeh.2000.1597.

    Article  CAS  PubMed  Google Scholar 

  50. Harkness KL, Stewart JG, Wynne-Edwards KE. Cortisol reactivity to social stress in adolescents: role of depression severity and child maltreatment. Psychoneuroendocrinology. 2011;36(2):173–81. https://doi.org/10.1016/j.psyneuen.2010.07.006.

    Article  CAS  PubMed  Google Scholar 

  51. Pilgrim K, Marin MF, Lupien SJ. Attentional orienting toward social stress stimuli predicts increased cortisol responsivity to psychosocial stress irrespective of the early socioeconomic status. Psychoneuroendocrinology. 2010;35(4):588–95. https://doi.org/10.1016/j.psyneuen.2009.09.015.

    Article  CAS  PubMed  Google Scholar 

  52. Vona-Davis L, Rose DP. The influence of socioeconomic disparities on breast cancer tumor biology and prognosis: a review. J Women's Health (Larchmt). 2009;18(6):883–93. https://doi.org/10.1089/jwh.2008.1127.

    Article  Google Scholar 

  53. Taylor TR, Williams CD, Makambi KH, Mouton C, Harrell JP, Cozier Y, et al. Racial discrimination and breast cancer incidence in US Black women: the black women's health study. Am J Epidemiol. 2007;166(1):46–54. https://doi.org/10.1093/aje/kwm056.

    Article  PubMed  Google Scholar 

  54. Liao MN, Chen MF, Chen SC, Chen PL. Uncertainty and anxiety during the diagnostic period for women with suspected breast cancer. Cancer Nurs. 2008;31(4):274–83. https://doi.org/10.1097/01.NCC.0000305744.64452.fe.

    Article  PubMed  Google Scholar 

  55. Sharp J, Zammit T, Azar T, Lawson D. Stress-like responses to common procedures in individually and group-housed female rats. Contemp Top Lab Anim Sci. 2003;42(1):9–18.

    CAS  PubMed  Google Scholar 

  56. Cora MC, Kooistra L, Travlos G. Vaginal cytology of the laboratory rat and mouse: Review and criteria for the staging of the estrous cycle using stained vaginal smears. Toxicol Pathol. 2015;43(6):776–93. https://doi.org/10.1177/0192623315570339.

    Article  CAS  PubMed  Google Scholar 

  57. Cavigelli SA, Yee JR, McClintock MK. Infant temperament predicts life span in female rats that develop spontaneous tumors. Horm Behav. 2006;50(3):454–62. https://doi.org/10.1016/j.yhbeh.2006.06.001.

    Article  PubMed  Google Scholar 

  58. Cavigelli SA, Monfort SL, Whitney TK, Mechref YS, Novotny M, McClintock MK. Frequent serial fecal corticoid measures from rats reflect circadian and ovarian corticosterone rhythms. J Endocrinol. 2005;184(1):153–63. https://doi.org/10.1677/joe.1.05935.

    Article  CAS  PubMed  Google Scholar 

  59. 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). https://doi.org/10.3791/2260.

  60. Ruifrok AC, Johnston DA. Quantification of histochemical staining by color deconvolution. Anal Quant Cytol Histol. 2001;23(4):291–9.

    CAS  PubMed  Google Scholar 

  61. Williams JB, Pang D, Delgado B, Kocherginsky M, Tretiakova M, Krausz T, et al. A model of gene-environment interaction reveals altered mammary gland gene expression and increased tumor growth following social isolation. Cancer Prev Res (Phila). 2009;2(10):850–61. https://doi.org/10.1158/1940-6207.CAPR-08-0238.

    Article  CAS  Google Scholar 

  62. Cavigelli SA, McClintock MK. Fear of novelty in infant rats predicts adult corticosterone dynamics and an early death. Proc Natl Acad Sci U S A. 2003;100(26):16131–6. https://doi.org/10.1073/pnas.2535721100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2014.

    Google Scholar 

  64. Hovey RC, McFadden TB, Akers RM. Regulation of mammary gland growth and morphogenesis by the mammary fat pad: a species comparison. J Mammary Gland Biol Neoplasia. 1999;4(1):53–68.

    Article  CAS  Google Scholar 

  65. Gjorevski N, Nelson CM. Integrated morphodynamic signalling of the mammary gland. Nat Rev Mol Cell Biol. 2011;12(9):581–93. https://doi.org/10.1038/nrm3168.

    Article  CAS  PubMed  Google Scholar 

  66. Roth KA, Katz RJ. Stress, behavioral arousal, and open field activity--a reexamination of emotionality in the rat. Neurosci Biobehav Rev. 1979;3(4):247–63.

    Article  CAS  Google Scholar 

  67. Selye H. The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol Metab. 1946;6:117–230. https://doi.org/10.1210/jcem-6-2-117.

    Article  CAS  PubMed  Google Scholar 

  68. Zehr JL, Gans SE, McClintock MK. Variation in reproductive traits is associated with short anogenital distance in female rats. Dev Psychobiol. 2001;38(4):229–38. https://doi.org/10.1002/dev.1017.

    Article  CAS  PubMed  Google Scholar 

  69. Romeo RD. Pubertal maturation and programming of hypothalamic-pituitary-adrenal reactivity. Front Neuroendocrinol. 2010;31(2):232–40. https://doi.org/10.1016/j.yfrne.2010.02.004.

    Article  CAS  PubMed  Google Scholar 

  70. Colditz GA, Wolin KY, Gehlert S. Applying what we know to accelerate cancer prevention. Sci Transl Med. 2012;4(127):127rv4. https://doi.org/10.1126/scitranslmed.3003218.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Cowie AT. The relative growth of the mammary gland in normal, gonadectomized and adrenalectomized rats. J Endocrinol. 1949;6(2):145–57.

    Article  CAS  Google Scholar 

  72. Macdonald GJ, Reece RP. Area measurement of the mammary glands of rats. J Dairy Sci. 1960;43:1658.

    Article  Google Scholar 

  73. Russo IH, Tewari M, Russo J. Morphology and development of the rat mammary gland. In: Jones TC, Mohr U, Hunt RD, editors. Integument and mammary glands. Berlin: Springer Berlin Heidelberg; 1989. p. 233–52.

    Chapter  Google Scholar 

  74. Gans SE, McClintock MK. Individual differences among female rats in the timing of the preovulatory lh surge are predicted by lordosis reflex intensity. Horm Behav. 1993;27(3):403–17.

    Article  CAS  Google Scholar 

  75. LeFevre J, McClintock MK. Isolation accelerates reproductive senescence and alters its predictors in female rats. Horm Behav. 1991;25(2):258–72.

    Article  CAS  Google Scholar 

  76. Beleut M, Rajaram RD, Caikovski M, Ayyanan A, Germano D, Choi Y, et al. Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci U S A. 2010;107(7):2989–94. https://doi.org/10.1073/pnas.0915148107.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Brisken C, Park S, Vass T, Lydon JP, O'Malley BW, Weinberg RA. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci U S A. 1998;95(9):5076–81.

    Article  CAS  Google Scholar 

  78. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Haslam SZ, Shyamala G. Progesterone receptors in normal mammary gland: receptor modulations in relation to differentiation. J Cell Biol. 1980;86(3):730–7.

    Article  CAS  Google Scholar 

  80. Sharma D, Smits BM, Eichelberg MR, Meilahn AL, Muelbl MJ, Haag JD, et al. Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats. PLoS One. 2011;6(10):e26145. https://doi.org/10.1371/journal.pone.0026145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shyamala G. Progesterone signaling and mammary gland morphogenesis. J Mammary Gland Biol Neoplasia. 1999;4(1):89–104.

    Article  CAS  Google Scholar 

  82. Romeo RD, Lee SJ, McEwen BS. Differential stress reactivity in intact and ovariectomized prepubertal and adult female rats. Neuroendocrinology. 2004;80(6):387–93. https://doi.org/10.1159/000084203.

    Article  CAS  PubMed  Google Scholar 

  83. Lee HJ, Gallego-Ortega D, Ledger A, Schramek D, Joshi P, Szwarc MM, et al. Progesterone drives mammary secretory differentiation via RankL-mediated induction of Elf5 in luminal progenitor cells. Development. 2013;140(7):1397–401. https://doi.org/10.1242/dev.088948.

    Article  CAS  PubMed  Google Scholar 

  84. McClintock MK. Social control of the ovarian cycle and the function of estrous synchrony. Am Zool. 1981;21(1):243–56.

    Article  Google Scholar 

  85. Aron C. Mechanisms of control of the reproductive function by olfactory stimuli in female mammals. Physiol Rev. 1979;59(2):229–84. https://doi.org/10.1152/physrev.1979.59.2.229.

    Article  CAS  PubMed  Google Scholar 

  86. Read LD, Snider CE, Miller JS, Greene GL, Katzenellenbogen BS. Ligand-modulated regulation of progesterone receptor messenger ribonucleic acid and protein in human breast cancer cell lines. Mol Endocrinol. 1988;2(3):263–71. https://doi.org/10.1210/mend-2-3-263.

    Article  CAS  PubMed  Google Scholar 

  87. Mahesh VB, Murphy LL, O'Conner JL. Selective modulation of FSH and LH secretion by steroids. Adv Exp Med Biol. 1987;219:131–52.

    Article  CAS  Google Scholar 

  88. Quinn MA, Xu X, Ronfani M, Cidlowski JA. Estrogen deficiency promotes hepatic steatosis via a glucocorticoid receptor-dependent mechanism in mice. Cell Rep. 2018;22(10):2690–701. https://doi.org/10.1016/j.celrep.2018.02.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wu W, Chaudhuri S, Brickley DR, Pang D, Karrison T, Conzen SD. Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells. Cancer Res. 2004;64(5):1757–64.

    Article  CAS  Google Scholar 

  90. Reichardt HM, Horsch K, Grone HJ, Kolbus A, Beug H, Hynes N, et al. Mammary gland development and lactation are controlled by different glucocorticoid receptor activities. Eur J Endocrinol. 2001;145(4):519–27.

    Article  CAS  Google Scholar 

  91. Whirledge S, Cidlowski JA. Glucocorticoids and reproduction: traffic control on the road to reproduction. Trends Endocrinol Metab. 2017;28(6):399–415. https://doi.org/10.1016/j.tem.2017.02.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Volden PA, Wonder EL, Skor MN, Carmean CM, Patel FN, Ye H, et al. Chronic social isolation is associated with metabolic gene expression changes specific to mammary adipose tissue. Cancer Prev Res (Phila). 2013;6(7):634–45. https://doi.org/10.1158/1940-6207.CAPR-12-0458.

    Article  CAS  Google Scholar 

  93. Volden PA, Skor MN, Johnson MB, Singh P, Patel FN, McClintock MK, et al. Mammary adipose tissue-derived lysophospholipids promote estrogen receptor-negative mammary epithelial cell proliferation. Cancer Prev Res (Phila). 2016;9(5):367–78. https://doi.org/10.1158/1940-6207.CAPR-15-0107.

    Article  CAS  Google Scholar 

  94. Honeth G, Schiavinotto T, Vaggi F, Marlow R, Kanno T, Shinomiya I, et al. Models of breast morphogenesis based on localization of stem cells in the developing mammary lobule. Stem Cell Reports. 2015;4(4):699–711. https://doi.org/10.1016/j.stemcr.2015.02.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Harris HR, Tamimi RM, Willett WC, Hankinson SE, Michels KB. Body size across the life course, mammographic density, and risk of breast cancer. Am J Epidemiol. 2011;174(8):909–18. https://doi.org/10.1093/aje/kwr225.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Bertrand KA, Baer HJ, Orav EJ, Klifa C, Shepherd JA, Van Horn L, et al. Body fatness during childhood and adolescence and breast density in young women: a prospective analysis. Breast Cancer Res. 2015;17:95. https://doi.org/10.1186/s13058-015-0601-4.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Drs. Terri Li and Gabrielle Baker for pathology expertise, and Dr. Paul Volden for sharing his expertise with the social isolation model. We are indebted to Mike McCarthy for Biopsychological Sciences Building operations crucial for this longitudinal research. This work was supported by National Institutes of Health (NIH) R01-CA148814 to SDC and MKM and The Institute for Mind and Biology, University of Chicago to MKM. Susan G. Komen GTDR16376189, Howard Hughes Medical Institute Med-into-Grad Scholars Program, NIH Grants T32-CA009594 and T32-DK087703 provided stipend support for MBJ. NIH P30-CA014599 supported The University of Chicago Comprehensive Cancer Center core facilities.

Author information

Authors and Affiliations

  1. Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL, USA

    Marianna B. Johnson, Sully Fernandez, Jordan W. Strober, Matthew J. Brady & Suzanne D. Conzen

  2. Department of Medicine, The University of Chicago, Chicago, IL, USA

    Marianna B. Johnson, Sully Fernandez, Jordan W. Strober, Ahmad B. Allaw, Matthew J. Brady & Suzanne D. Conzen

  3. Institute for Mind and Biology, The University of Chicago, Chicago, IL, USA

    Joscelyn N. Hoffmann, Hannah M. You & Martha K. McClintock

  4. Department of Pathology, The University of Chicago, Chicago, IL, USA

    Ricardo R. Lastra

  5. Ben May Department of Cancer Research, The University of Chicago, Chicago, IL, USA

    Suzanne D. Conzen

  6. Departments of Psychology and Comparative Human Development, The University of Chicago, 940 East 57th Street, Chicago, IL, 60637, USA

    Martha K. McClintock

Authors
  1. Marianna B. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joscelyn N. Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hannah M. You
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ricardo R. Lastra
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sully Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jordan W. Strober
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ahmad B. Allaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matthew J. Brady
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Suzanne D. Conzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Martha K. McClintock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martha K. McClintock.

Ethics declarations

National Institutes of Health and University of Chicago Animal Care Guidelines were followed for the use of animals in all studies.

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic Supplementary Material

ESM 1

Supplemental Fig. 1 Mammary gland (MG) whole mounts. Representative digital images of right inguinal MG of rats aged 8, 13, 17, 21, and 25 weeks, after exposure to grouped or isolated social condition since weaning. Dashed line indicates perimeter of mammary ductal tree. Scale bars, 5 mm.

Supplemental Fig. 2 Color deconvolution for quantification of mammary gland (MG) structures. Ductal structures, stroma, and adipose tissue. A representative section of a left inguinal MG (H&E stain), hematoxylin stains ductal structures purple, eosin stains stroma and blood vessels pink, and unstained white adipose tissue.

Supplemental Fig. 3 Association between mammary gland stroma and ductal structures in grouped and isolated rats. Correlation between stroma and ductal structures observed on H&E slides at 17, 21, and 25 weeks of age; R = 0.70, *** P < 0.001, n = 26.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Johnson, M.B., Hoffmann, J.N., You, H.M. et al. Psychosocial Stress Exposure Disrupts Mammary Gland Development. J Mammary Gland Biol Neoplasia 23, 59–73 (2018). https://doi.org/10.1007/s10911-018-9392-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-018-9392-4

Keywords

Search

Navigation