Hormonal Regulation of the Immune Microenvironment in the Mammary Gland

  • Eleanor F. Need
  • Vahid Atashgaran
  • Wendy V. Ingman
  • Pallave Dasari


It is well established that the development and homeostasis of the mammary gland are highly dependent upon the actions of ovarian hormones progesterone and estrogen, as well as the availability of prolactin for the pregnant and lactating gland. More recently it has become apparent that immune system cells and cytokines play essential roles in both mammary gland development as well as breast cancer. Here, we review hormonal effects on mammary gland biology during puberty, menstrual cycling, pregnancy, lactation and involution, and dissect how hormonal control of the immune system may contribute to mammary development at each stage via cytokine secretion and recruitment of macrophages, eosinophils, mast cells and lymphocytes. Collectively, these alterations may create an immunotolerant or inflammatory immune environment at specific developmental stages or phases of the menstrual cycle. Of particular interest for further research is investigation of the combinatorial actions of progesterone and estrogen during the luteal phase of the menstrual cycle and key developmental points where the immune system may play an active role both in mammary development as well as in the creation of an immunotolerant environment, thereby affecting breast cancer risk.


Progesterone Estrogen Macrophage T cell Cytokine 



Androgen receptor


Cyclooxygenase-2 enzyme


Colony-stimulating factor


Epidermal growth factor receptor


Estrogen receptor alpha


Interferon gamma




Inhibitor of NF-κB




Nuclear factor kappa B


Progesterone receptor


Receptor activator of NF-κB


Receptor activator of NF-κB ligand


Terminal ductal lobular units


Terminal end buds


Helper T lymphocytes


Toll-like receptor


Tumor necrosis factor alpha


Regulatory T lymphocytes


  1. 1.
    Coussens LM, Pollard JW. Leukocytes in Mammary Development and Cancer. Cold Spring Harbor Perspectives in Biology. 2011;3(3). doi:10.1101/cshperspect.a003285.
  2. 2.
    Chua AC, Hodson LJ, Moldenhauer LM, Robertson SA, Ingman WV. Dual roles for macrophages in ovarian cycle-associated development and remodelling of the mammary gland epithelium. Development. 2010;137(24):4229–38. doi:10.1242/dev.059261.PubMedCrossRefGoogle Scholar
  3. 3.
    Aupperlee MD, Zhao Y, Tan YS, Leipprandt JR, Bennett J, Haslam SZ et al. Epidermal growth factor receptor (EGFR)-signaling is a key mediator of hormone-induced leukocyte infiltration in the pubertal female mammary gland. Endocrinology. 2014:en20131933. doi:10.1210/en.2013-1933.
  4. 4.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.PubMedCrossRefGoogle Scholar
  5. 5.
    Prieto GA, Rosenstein Y. Oestradiol potentiates the suppressive function of human CD4 CD25 regulatory T cells by promoting their proliferation. Immunology. 2006;118(1):58–65. doi:10.1111/j.1365-2567.2006.02339.x.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Lee JH, Lydon JP, Kim CH. Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability. Eur J Immunol. 2012. doi:10.1002/eji.201142317.Google Scholar
  7. 7.
    Brisken C. Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer. 2013;13(6):385–96. doi:10.1038/nrc3518.PubMedCrossRefGoogle Scholar
  8. 8.
    Cancer CGoHFiB. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13(11):1141–51. doi:10.1016/S1470-2045(12)70425-4.CrossRefGoogle Scholar
  9. 9.
    Chlebowski RT, Anderson GL, Gass M, et al. EStrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684–92. doi:10.1001/jama.2010.1500.PubMedCrossRefGoogle Scholar
  10. 10.
    Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SA, Brzyski R, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299(9):1036–45. doi:10.1001/jama.299.9.1036.PubMedCrossRefGoogle Scholar
  11. 11.
    LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: A randomized controlled trial. JAMA. 2011;305(13):1305–14. doi:10.1001/jama.2011.382.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Pike MC, Spicer DV, Dahmoush L, Press MF. Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev. 1993;15(1):17–35.PubMedGoogle Scholar
  13. 13.
    Pollard JW, Hennighausen L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc Natl Acad Sci U S A. 1994;91(20):9312–6.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Hodson LJ, Chua AC, Evdokiou A, Robertson SA, Ingman WV. Macrophage phenotype in the mammary gland fluctuates over the course of the estrous cycle and is regulated by ovarian steroid hormones. Biol Reprod. 2013;89(3):65. doi:10.1095/biolreprod.113.109561.PubMedCrossRefGoogle Scholar
  15. 15.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69. doi:10.1038/nri2448.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Xue J, Schmidt Susanne V, Sander J, Draffehn A, Krebs W, Quester I, et al. Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation. Immunity. 2014;40(2):274–88. doi:10.1016/j.immuni.2014.01.006.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17(3):138–46.PubMedCrossRefGoogle Scholar
  18. 18.
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87. doi:10.1016/j.cell.2008.05.009.PubMedCrossRefGoogle Scholar
  19. 19.
    Lwin KY, Sloane JP, Zuccarini O, Beverley PC. An immunohistological study of leukocyte localization in benign and malignant breast tissue. Int J Cancer. 1985;36(4):433–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Zuk JA, Walker RA. Immunohistochemical analysis of HLA antigens and mononuclear infiltrates of benign and malignant breast. J Pathol. 1987;152(4):275–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol. 2006;24:147–74. doi:10.1146/annurev.immunol.24.021605.090720.PubMedCrossRefGoogle Scholar
  22. 22.
    Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev. 1997;77(4):1033–79.PubMedGoogle Scholar
  23. 23.
    Russo J, Tay LK, Russo IH. Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat. 1982;2(1):5–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Cardiff R, Wellings S. The Comparative Pathology of Human and Mouse Mammary Glands. J Mammary Gland Biol Neoplasia. 1999;4(1):105–22. doi:10.1023/a:1018712905244.PubMedCrossRefGoogle Scholar
  25. 25.
    Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A. 2006;103(7):2196–201.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Nautiyal J, Steel JH, Mane MR, Oduwole O, Poliandri A, Alexi X, et al. The transcriptional co-factor RIP140 regulates mammary gland development by promoting the generation of key mitogenic signals. Development. 2013;140(5):1079–89.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Xu J, Liao L, Ning G, Yoshida-Komiya H, Deng C, O'Malley BW. The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc Natl Acad Sci. 2000;97(12):6379–84.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, et al. Generation and reproductive phenotypes of mice lacking estrogen receptor β. Proc Natl Acad Sci. 1998;95(26):15677–82.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Yeh S, Tsai M-Y, Xu Q, Mu X-M, Lardy H, Huang K-E, et al. Generation and characterization of androgen receptor knockout (ARKO) mice: An in vivo model for the study of androgen functions in selective tissues. Proc Natl Acad Sci. 2002;99(21):13498–503. doi:10.1073/pnas.212474399.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Peters AA, Ingman WV, Tilley WD, Butler LM. Differential effects of exogenous androgen and an androgen receptor antagonist in the peri- and postpubertal murine mammary gland. Endocrinology. 2011;152(10):3728–37. doi:10.1210/en.2011-1133.PubMedCrossRefGoogle Scholar
  31. 31.
    Ciarloni L, Mallepell S, Brisken C. Amphiregulin is an essential mediator of estrogen receptor α function in mammary gland development. Proc Natl Acad Sci. 2007;104(13):5455–60.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Wiesen JF, Young P, Werb Z, Cunha GR. Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. Development. 1999;126(2):335–44.PubMedGoogle Scholar
  33. 33.
    Gallego MI, Binart N, Robinson GW, Okagaki R, Coschigano KT, Perry J, et al. Prolactin, Growth Hormone, and Epidermal Growth Factor Activate Stat5 in Different Compartments of Mammary Tissue and Exert Different and Overlapping Developmental Effects. Dev Biol. 2001;229(1):163–75. doi:10.1006/dbio.2000.9961.PubMedCrossRefGoogle Scholar
  34. 34.
    Van Nguyen A, Pollard JW. Colony stimulating factor-1 is required to recruit macrophages into the mammary gland to facilitate mammary ductal outgrowth. Dev Biol. 2002;247(1):11–25. doi:10.1006/dbio.2002.0669.PubMedCrossRefGoogle Scholar
  35. 35.
    Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary gland development requires macrophages and eosinophils. Development. 2000;127(11):2269–82.PubMedGoogle Scholar
  36. 36.
    Ingman WV, Wyckoff J, Gouon-Evans V, Condeelis J, Pollard JW. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev Dyn. 2006;235(12):3222–9. doi:10.1002/dvdy.20972.PubMedCrossRefGoogle Scholar
  37. 37.
    Fleming JM, Miller TC, Kidacki M, Ginsburg E, Stuelten CH, Stewart DA, et al. Paracrine interactions between primary human macrophages and human fibroblasts enhance murine mammary gland humanization in vivo. Breast Cancer Res. 2012;14(3):R97. doi:10.1186/bcr3215.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Sferruzzi-Perri AN, Robertson SA, Dent LA. Interleukin-5 transgene expression and eosinophilia are associated with retarded mammary gland development in mice. Biol Reprod. 2003;69(1):224–33. doi:10.1095/biolreprod.102.010611.PubMedCrossRefGoogle Scholar
  39. 39.
    Lilla JN, Werb Z. Mast cells contribute to the stromal microenvironment in mammary gland branching morphogenesis. Dev Biol. 2010;337(1):124–33. doi:10.1016/j.ydbio.2009.10.021.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Fanger H, Ree HJ. Cyclic changes of human mammary gland epithelium in relation to the menstrual cycle—an ultrastructural study. Cancer. 1974;34(3):574–85.CrossRefGoogle Scholar
  41. 41.
    Vogel P, Georgiade N, Fetter B, Vogel F, McCarty Jr K. The correlation of histologic changes in the human breast with the menstrual cycle. Am J Pathol. 1981;104(1):23.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Fata JE, Chaudhary V, Khokha R. Cellular turnover in the mammary gland is correlated with systemic levels of progesterone and not 17β-estradiol during the estrous cycle. Biol Reprod. 2001;65(3):680–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Navarrete M, Maier CM, Falzoni R, Quadros L, Lima GR, Baracat EC, et al. Assessment of the proliferative, apoptotic and cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle. Breast Cancer Res. 2005;7(3):R306–13.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Söderqvist G, Isaksson E, von Schoultz B, Carlström K, Tani E, Skoog L. Proliferation of breast epithelial cells in healthy women during the menstrual cycle. Am J Obstet Gynecol. 1997;176(1):123–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Potten CS, Watson R, Williams G, Tickle S, Roberts SA, Harris M, et al. The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer. 1988;58(2):163.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Ramakrishnan R, Khan SA, Badve S. Morphological changes in breast tissue with menstrual cycle. Mod Pathol. 2002;15(12):1348–56. doi:10.1097/01.MP.0000039566.20817.46.PubMedCrossRefGoogle Scholar
  47. 47.
    Fata JE, Chaudhary V, Khokha R. Cellular turnover in the mammary gland is correlated with systemic levels of progesterone and not 17beta-estradiol during the estrous cycle. Biol Reprod. 2001;65(3):680–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Walker NI, Bennett RE, Kerr JF. Cell death by apoptosis during involution of the lactating breast in mice and rats. Am J Anat. 1989;185(1):19–32.PubMedCrossRefGoogle Scholar
  49. 49.
    Diefenbach A, Jamieson AM, Liu SD, Shastri N, Raulet DH. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol. 2000;1(2):119–26.PubMedCrossRefGoogle Scholar
  50. 50.
    Murphy AJ, Guyre PM, Pioli PA. Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. J Immunol. 2010;184(9):5029–37. doi:10.4049/jimmunol.0903463.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Ribas V, Drew BG, Le JA, Soleymani T, Daraei P, Sitz D, et al. Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc Natl Acad Sci U S A. 2011;108(39):16457–62. doi:10.1073/pnas.1104533108.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature. 1997;390(6658):350–1. doi:10.1038/37022.PubMedCrossRefGoogle Scholar
  53. 53.
    Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101(4):890–8. doi:10.1172/jci1112.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Masso-Welch PA, Merhige PM, Veeranki OL, Kuo SM. Loss of IL-10 decreases mouse postpubertal mammary gland development in the absence of inflammation. Immunol Investig. 2012;41(5):521–37. doi:10.3109/08820139.2012.684193.CrossRefGoogle Scholar
  55. 55.
    Lindsey WF, Das Gupta TK, Beattie CW. Influence of the Estrous Cycle during Carcinogen Exposure on Nitrosomethylurea-induced Rat Mammary Carcinoma. Cancer Res. 1981;41(10):3857–62.PubMedGoogle Scholar
  56. 56.
    Smith M, Freeman M, Neill J. The Control of Progesterone Secretion During the Estrous Cycle and Early Pseudopregnancy in the Rat: Prolactin, Gonadotropin and Steroid Levels Associated with Rescue of the Corpus Luteum of Pseudopregnancy 1 2. Endocrinology. 1975;96(1):219–26.PubMedCrossRefGoogle Scholar
  57. 57.
    Faas M, Bouman A, Moesa H, Heineman MJ, de Leij L, Schuiling G. The immune response during the luteal phase of the ovarian cycle: a Th2-type response? Fertil Steril. 2000;74(5):1008–13.PubMedCrossRefGoogle Scholar
  58. 58.
    Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, et al. Cutting edge: estrogen drives expansion of the CD4+ CD25+ regulatory T cell compartment. J Immunol. 2004;173(4):2227–30.PubMedCrossRefGoogle Scholar
  59. 59.
    Arruvito L, Sanz M, Banham AH, Fainboim L. Expansion of CD4 + CD25 + and FOXP3+ regulatory T cells during the follicular phase of the menstrual cycle: implications for human reproduction. J Immunol. 2007;178(4):2572–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Dasari P, Sharkey DJ, Noordin E, Glynn DJ, Hodson LJ, Chin PY, et al. Hormonal regulation of the cytokine microenvironment in the mammary gland Manuscript submitted. 2014.Google Scholar
  61. 61.
    Brannstrom M, Friden BE, Jasper M, Norman RJ. Variations in peripheral blood levels of immunoreactive tumor necrosis factor alpha (TNFalpha) throughout the menstrual cycle and secretion of TNFalpha from the human corpus luteum. Eur J Obstet Gynecol Reprod Biol. 1999;83(2):213–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Angstwurm MW, Gartner R, Ziegler-Heitbrock HW. Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine. 1997;9(5):370–4. doi:10.1006/cyto.1996.0178.PubMedCrossRefGoogle Scholar
  63. 63.
    Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci. 2003;100(17):9744–9.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Leong DA, Frawley LS, Neill JD. Neuroendocrine control of prolactin secretion. Annu Rev Physiol. 1983;45(1):109–27.PubMedCrossRefGoogle Scholar
  65. 65.
    Srivastava S, Matsuda M, Hou Z, Bailey JP, Kitazawa R, Herbst MP, et al. Receptor activator of NF-κB ligand induction via Jak2 and Stat5a in mammary epithelial cells. J Biol Chem. 2003;278(46):46171–8.PubMedCrossRefGoogle Scholar
  66. 66.
    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. 2010;107(7):2989–94. doi:10.1073/pnas.0915148107.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Fernandez-Valdivia R, Mukherjee A, Ying Y, Li J, Paquet M, DeMayo FJ, et al. The RANKL signaling axis is sufficient to elicit ductal side-branching and alveologenesis in the mammary gland of the virgin mouse. Dev Biol. 2009;328(1):127–39.PubMedCrossRefGoogle Scholar
  68. 68.
    Cao Y, Bonizzi G, Seagroves TN, Greten FR, Johnson R, Schmidt EV, et al. IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell. 2001;107(6):763–75.PubMedCrossRefGoogle Scholar
  69. 69.
    Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 1995;9(19):2364–72.PubMedCrossRefGoogle Scholar
  70. 70.
    Fornetti J, Jindal S, Middleton KA, Borges VF, Schedin P. Physiological COX-2 Expression in Breast Epithelium Associates with COX-2 Levels in Ductal Carcinoma < i > in Situ</i > and Invasive Breast Cancer in Young Women. Am J Pathol. 2014;184(4):1219–29.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhu Y, Wu M, Wu CY, Xia GQ. Role of progesterone in TLR4-MyD88-dependent signaling pathway in pre-eclampsia. J Huazhong Univ Sci Technol Med Sci. 2013;33(5):730–4. doi:10.1007/s11596-013-1188-6.PubMedCrossRefGoogle Scholar
  72. 72.
    Sapi E, Flick MB, Rodov S, Carter D, Kacinski BM. Expression of CSF-I and CSF-I receptor by normal lactating mammary epithelial cells. J Soc Gynecol Investig. 1998;5(2):94–101. doi:10.1016/s1071-5576(97)00108-1.PubMedCrossRefGoogle Scholar
  73. 73.
    Günzel D, Alan S. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93(2):525–69.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Kobayashi K, Oyama S, Numata A, Rahman MM, Kumura H. Lipopolysaccharide Disrupts the Milk-Blood Barrier by Modulating Claudins in Mammary Alveolar Tight Junctions. PLoS One. 2013;8(4):e62187. doi:10.1371/journal.pone.0062187.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Gonen E, Vallon-Eberhard A, Elazar S, Harmelin A, Brenner O, Rosenshine I, et al. Toll-like receptor 4 is needed to restrict the invasion of Escherichia coli P4 into mammary gland epithelial cells in a murine model of acute mastitis. Cell Microbiol. 2007;9(12):2826–38. doi:10.1111/j.1462-5822.2007.00999.x.PubMedCrossRefGoogle Scholar
  76. 76.
    Glynn DJ, Hutchinson MR, Ingman WV. Toll-Like Receptor 4 Regulates Lipopolysaccharide-Induced Inflammation and Lactation Insufficiency in a Mouse Model of Mastitis. Biol Reprod. 2014. doi:10.1095/biolreprod.114.117663.PubMedGoogle Scholar
  77. 77.
    Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol. 2004;5(3):266–71.PubMedCrossRefGoogle Scholar
  78. 78.
    Xing D, Oparil S, Yu H, Gong K, Feng W, Black J, et al. Estrogen modulates NFkappaB signaling by enhancing IkappaBalpha levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor-beta. PLoS One. 2012;7(6):e36890. doi:10.1371/journal.pone.0036890.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Sigl V, Penninger JM. RANKL/RANK—From bone physiology to breast cancer. Cytokine Growth Factor Rev. 2014;25(2):205–14. doi:10.1016/j.cytogfr.2014.01.002.PubMedCrossRefGoogle Scholar
  80. 80.
    Mackern-Oberti JP, Valdez SR, Vargas-Roig LM, Jahn GA. Impaired mammary gland T cell population during early lactation in hypoprolactinemic lactation-deficient rats. Reproduction (Cambridge, England). 2013;146(3):233–42. doi:10.1530/rep-12-0387.CrossRefGoogle Scholar
  81. 81.
    Khaled WT, Read EK, Nicholson SE, Baxter FO, Brennan AJ, Came PJ, et al. The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development. Development. 2007;134(15):2739–50. doi:10.1242/dev.003194.PubMedCrossRefGoogle Scholar
  82. 82.
    Miyaura H, Iwata M. Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol. 2002;168(3):1087–94.PubMedCrossRefGoogle Scholar
  83. 83.
    Radisky DC, Hartmann LC. Mammary involution and breast cancer risk: transgenic models and clinical studies. J Mammary Gland Biol Neoplasia. 2009;14(2):181–91.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Chapman RS, Lourenco PC, Tonner E, Flint DJ, Selbert S, Takeda K, et al. Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev. 1999;13(19):2604–16.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Bierie B, Gorska AE, Stover DG, Moses HL. TGF‐β promotes cell death and suppresses lactation during the second stage of mammary involution. J Cell Physiol. 2009;219(1):57–68.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    O'Brien J, Martinson H, Durand-Rougely C, Schedin P. Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution. Development. 2012;139(2):269–75.PubMedCrossRefGoogle Scholar
  87. 87.
    O'Brien J, Martinson H, Durand-Rougely C, Schedin P. Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution. Development. 2011. doi:10.1242/dev.071696.PubMedGoogle Scholar
  88. 88.
    O'Brien J, Lyons T, Monks J, Lucia MS, Wilson RS, Hines L, et al. Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. Am J Pathol. 2010;176(3):1241–55. doi:10.2353/ajpath.2010.090735.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 2010;468(7320):98–102.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468(7320):103–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Tanos T, Sflomos G, Echeverria PC, Ayyanan A, Gutierrez M, Delaloye J-F, et al. Progesterone/RANKL Is a Major Regulatory Axis in the Human Breast. Sci Transl Med. 2013;5(182):182ra55. doi:10.1126/scitranslmed.3005654.PubMedCrossRefGoogle Scholar
  92. 92.
    Wood CE, Branstetter D, Jacob AP, Cline JM, Register TC, Rohrbach K, et al. Progestin effects on cell proliferation pathways in the postmenopausal mammary gland. Breast Cancer Res. 2013;15(4):R62.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Stute P, Sielker S, Wood CE, Register TC, Lees CJ, Dewi FN, et al. Life stage differences in mammary gland gene expression profile in non-human primates. Breast Cancer Res Treat. 2012;133(2):617–34.PubMedCrossRefGoogle Scholar
  94. 94.
    Dep Prete A, Allavena P, Santoro G, Fumarulo R, Corsi MM, Mantovani A. Molecular pathways in cancer-related inflammation. Biochemia Medica. 2011;21(3):264–75.CrossRefGoogle Scholar
  95. 95.
    Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature. 2011;470(7335):548–53. doi:10.1038/nature09707.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Loser K, Mehling A, Loeser S, Apelt J, Kuhn A, Grabbe S, et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med. 2006;12(12):1372–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Anderson T, Ferguson D, Raab G. Cell turnover in the“ resting” human breast: influence of parity, contraceptive pill, age and laterality. Br J Cancer. 1982;46(3):376.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Eleanor F. Need
    • 1
    • 2
  • Vahid Atashgaran
    • 1
    • 2
  • Wendy V. Ingman
    • 1
    • 2
    • 3
  • Pallave Dasari
    • 1
    • 2
  1. 1.Discipline of Surgery, School of Medicine, The Queen Elizabeth HospitalUniversity of AdelaideWoodvilleAustralia
  2. 2.Robinson Research InstituteUniversity of AdelaideAdelaideAustralia
  3. 3.School of Paediatrics and Reproductive HealthUniversity of AdelaideAdelaideAustralia

Personalised recommendations