Anatomy and Physiology of the Breast

  • Martha C. Johnson
  • Mary L. CutlerEmail author


The mammary gland is classified as a branched tubuloalveolar structure with hormone-responsive lobules surrounded by a loose connective tissue stroma. The glands making up the breast are embedded in adipose tissue separated by bands of connective tissue. The breast is unique in that it completes the majority of its development after birth undergoing hormonally regulated changes during puberty. It varies moderately during each menstrual cycle, develops additionally during pregnancy, and differentiates following parturition during the process of lactation. The breast regresses after lactation to a much less differentiated state through the process of involution, which occurs following each cycle of pregnancy, parturition, and lactation. Following reduction of estrogen and progesterone at menopause, the breast involutes, reverting to a near prepubertal structure. These complex developmental processes are controlled by a combination of hormonal stimulation, growth factors, and other physical elements constituting the microenvironment of the mammary gland.


Breast Mammary Development Mammary alveoli Lactation Involution Hormone (Estrogen, growth hormone, gonadotropin-releasing hormone, prolactin, oxytocin) 



B-cell CLL/lymphoma 2


Breast cancer 1


Basement membrane




Cluster of differentiation


Colony-stimulating factor


Connective tissue growth factor




Extracellular matrix


Epidermal growth factor


Epidermal growth factor receptor


Estrogen receptor


Fibroblast growth factor


Follicle-stimulating hormone


Growth hormone


Gonadotropin-releasing hormone


Human chorionic gonadotropin


Hepatocyte growth factor


Hypoxia-inducible factor




Human placental lactogen


Interstitial cell of Cajal


Immunoglobulin A


Insulin-like growth factor


IGF-binding protein


Immunoglobulin M


Insulin receptor


Janus kinase


A nuclear antigen in cycling cells


Luteinizing hormone


Matrix metalloproteinases




Progesterone receptor




Prolactin receptor


Parathyroid hormone


Parathyroid hormone-related peptide


Stem cell antigen


Side population


Signal transducer and activator of transcription


Terminal ductal lobular unit


Terminal end bud



We remain extremely grateful to colleagues for their critical reading of the original chapter, and we again thank Richard Conran, M.D. Ph.D., J.D., and Stephen Rothwell, Ph.D., for providing specimens for the micrographs included herein.


The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences.


  1. 1.
    Romer AS. The vertebrate body. 4th ed. Philadelphia: W. B. Saunders Company; 1970.Google Scholar
  2. 2.
    Swaminathan N. Strange but true: males can lactate. Sci Am. 2007. Available from:
  3. 3.
    Wuringer E, Mader N, Posch E, Holle J. Nerve and vessel supplying ligamentous suspension of the mammary gland. Plast Reconstr Surg. 1998;101(6):1486–93.PubMedCrossRefGoogle Scholar
  4. 4.
    Stranding S, editor. Gray’s anatomy: the anatomical basis of clinical practice. 39th ed. Elsevier, Churchill, Livingstone: Edinburgh; 2005.Google Scholar
  5. 5.
    Moore KA. Clinically oriented anatomy. 5th ed. Baltimore: Lipincott Williams and Wilkins; 2006.Google Scholar
  6. 6.
    Sarhadi NS, Shaw-Dunn J, Soutar DS. Nerve supply of the breast with special reference to the nipple and areola: Sir Astley Cooper revisited. Clin Anat. 1997;10(4):283–8.Google Scholar
  7. 7.
    Schlenz I, Kuzbari R, Gruber H, Holle J. The sensitivity of the nipple-areola complex: an anatomic study. Plast Reconstr Surg. 2000;105(3):905–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Jaspars JJ, Posma AN, van Immerseel AA, Gittenberger-de Groot AC. The cutaneous innervation of the female breast and nipple-areola complex: implications for surgery. Br J Plast Surg. 1997;50(4):249–59.Google Scholar
  9. 9.
    Schlenz I, Rigel S, Schemper M, Kuzbari R. Alteration of nipple and areola sensitivity by reduction mammaplasty: a prospective comparison of five techniques. Plast reconstructive surgery. 2005;115(3):743–51; discussion 52–4.Google Scholar
  10. 10.
    Wakerley JB. Milk ejection and its control. In: Neill JD, editor. Knobil and Neill’s physiology. 3 ed. Amsterdam: Elsevier; 2006. p. 3129–90.Google Scholar
  11. 11.
    DelVecchyo C, Caloca J Jr, Caloca J, Gomez-Jauregui J. Evaluation of breast sensibility using dermatomal somatosensory evoked potentials. Plast Reconstr Surg. 2004;113(7):1975–83.PubMedCrossRefGoogle Scholar
  12. 12.
    Godwin Y, Valassiadou K, Lewis S, Denley H. Investigation into the possible cause of subjective decreased sensory perception in the nipple-areola complex of women with macromastia. Plast Reconstr Surg. 2004;113(6):1598–606.PubMedCrossRefGoogle Scholar
  13. 13.
    Bloom WD. A textbook of histology. 10th ed. Philadelphia: W. B. Saunders Company; 1975.Google Scholar
  14. 14.
    Franke-Radowiecka A, Wasowicz K. Adrenergic and cholinergic innervation of the mammary gland in the pig. Anat Histol Embryol. 2002;31(1):3–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Papay FA, Verghese A, Stanton-Hicks M, Zins J. Complex regional pain syndrome of the breast in a patient after breast reduction. Ann Plast Surg. 1997;39(4):347–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Eriksson M, Lindh B, Uvnas-Moberg K, Hokfelt T. Distribution and origin of peptide-containing nerve fibres in the rat and human mammary gland. Neuroscience. 1996;70(1):227–45.PubMedCrossRefGoogle Scholar
  17. 17.
    Ricbourg B. [Applied anatomy of the breast: blood supply and innervation]. Annales de chirurgie plastique et esthetique. 1992;37(6):603–20. Anatomie appliquee du sein. Vascularisation et innervation.Google Scholar
  18. 18.
    Naccarato AG, Viacava P, Bocci G, Fanelli G, Aretini P, Lonobile A, et al. Definition of the microvascular pattern of the normal human adult mammary gland. J Anat. 2003;203(6):599–603.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Weinstein SP, Conant EF, Sehgal CM, Woo IP, Patton JA. Hormonal variations in the vascularity of breast tissue. J Ultrasound Med. 2005;24(1):67–72; quiz 4.Google Scholar
  20. 20.
    O’Rahilly M, Mueller F, Carpenter S, Swenson R. Vessels, lymphatic drainage and the breast. Hanover, NH: Dartmouth Medical School Publ; 2004.Google Scholar
  21. 21.
    Nathanson SD, Wachna DL, Gilman D, Karvelis K, Havstad S, Ferrara J. Pathways of lymphatic drainage from the breast. Ann Surg Oncol. 2001;8(10):837–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Braithwaite LR. The flow of lymph from the ileocaecal angel, and its possible bearing on the cause of duodenal and gastric ulcer. Br J Surg. 1923;11:7–26.CrossRefGoogle Scholar
  23. 23.
    Krag D, Weaver D, Ashikaga T, Moffat F, Klimberg VS, Shriver C, et al. The sentinel node in breast cancer–a multicenter validation study. N Engl J Med. 1998;339(14):941–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Estourgie SH, Nieweg OE, Olmos RA, Rutgers EJ, Kroon BB. Lymphatic drainage patterns from the breast. Ann Surg. 2004;239(2):232–7.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Vendrell-Torne E, Setoain-Quinquer J, Domenech-Torne FM. Study of normal mammary lymphatic drainage using radioactive isotopes. J Nuclear Med. 1971;13(11):801–5.Google Scholar
  26. 26.
    Suami H, Pan WR, Mann GB, Taylor GI. The lymphatic anatomy of the breast and its implications for sentinel lymph node biopsy: a human cadaver study. Ann Surg Oncol. 2008;15(3):863–71.Google Scholar
  27. 27.
    Krynyckyi BR, Shim J, Kim CK. Internal mammary chain drainage of breast cancer. Ann Surg. 2004;240(3):557; author reply 8.Google Scholar
  28. 28.
    Kellokumpu-Lehtinen P, Johansson RM, Pelliniemi LJ. Ultrastructure of human fetal mammary gland. Anat Rec. 1987;218(1):66–72.PubMedCrossRefGoogle Scholar
  29. 29.
    Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics. 1997;99(4):505–12.PubMedCrossRefGoogle Scholar
  30. 30.
    Tanner J. Growth at adolescence. 2nd ed. Oxford: Blackwell Scientific Publications; 1962.Google Scholar
  31. 31.
    Tavassoli FA. Pathology of the breast. 2nd ed. Stamford, CT: Appleton & Lange; 1999.Google Scholar
  32. 32.
    Hussain Z, Roberts N, Whitehouse GH, Garcia-Finana M, Percy D. Estimation of breast volume and its variation during the menstrual cycle using MRI and stereology. Br J Radiol. 1999;72(855):236–45.PubMedCrossRefGoogle Scholar
  33. 33.
    Howard BA, Gusterson BA. Human breast development. J Mammary Gland Biol Neoplasia. 2000;5(2):119–37.PubMedCrossRefGoogle Scholar
  34. 34.
    Nelson CM, Bissell MJ. Modeling dynamic reciprocity: engineering three-dimensional culture models of breast architecture, function, and neoplastic transformation. Semin Cancer Biol. 2005;15(5):342–52.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Rosen PR. Rosen’s breast pathology. 2nd ed. Philadelphia: Lippincott williams & Wilkins; 2001.Google Scholar
  36. 36.
    Pitelka DR. The mammary gland. In: Weiss L, editor. Cell and tissue biology: a textbook of histology. 6th ed. New York: Elsevier Biomedical; 1988. p. 880–98.Google Scholar
  37. 37.
    Pathology UoVDo. I. Gross anatomy and histology. Charlottesville 1998–2007; Available from:
  38. 38.
    Cardiff RD. Are the TDLU of the human the same as the LA of mice? J Mammary Gland Biol Neoplasia. 1998;3(1):3–5.Google Scholar
  39. 39.
    Moffat DF, Going JJ. Three dimensional anatomy of complete duct systems in human breast: pathological and developmental implications. J Clin Pathol. 1996;49(1):48–52.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ohtake T, Kimijima I, Fukushima T, Yasuda M, Sekikawa K, Takenoshita S, et al. Computer-assisted complete three-dimensional reconstruction of the mammary ductal/lobular systems: implications of ductal anastomoses for breast-conserving surgery. Cancer. 2001;91(12):2263–72.PubMedCrossRefGoogle Scholar
  41. 41.
    Junqueira LJ. Basic histology text and atlas. 10th ed. New York: Lange Medical Books McGraw-Hill; 2003.Google Scholar
  42. 42.
    Ferguson DJ. Intraepithelial lymphocytes and macrophages in the normal breast. Virchows Arch. 1985;407(4):369–78.CrossRefGoogle Scholar
  43. 43.
    Ross M, Pawlina W. Histology, a text and atlas. 5th ed. Baltimore: Lippincott Williams & Wilkins; 2006.Google Scholar
  44. 44.
    Daniel CW, Strickland P, Friedmann Y. Expression and functional role of E- and P-cadherins in mouse mammary ductal morphogenesis and growth. Dev Biol. 1995;169(2):511–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Deugnier MA, Teuliere J, Faraldo MM, Thiery JP, Glukhova MA. The importance of being a myoepithelial cell. Breast Cancer Res. 2002;4(6):224–30.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Woodward WA, Chen MS, Behbod F, Rosen JM. On mammary stem cells. J Cell Sci. 2005;118(Pt 16):3585–94.PubMedCrossRefGoogle Scholar
  47. 47.
    Monaghan P, Moss D. Connexin expression and gap junctions in the mammary gland. Cell Biol Int. 1996;20(2):121–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Schmeichel KL, Weaver VM, Bissell MJ. Structural cues from the tissue microenvironment are essential determinants of the human mammary epithelial cell phenotype. J Mammary Gland Biol Neoplasia. 1998;3(2):201–13.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Glukhova M, Koteliansky V, Sastre X, Thiery JP. Adhesion systems in normal breast and in invasive breast carcinoma. Am J Pathol. 1995;146(3):706–16.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Gudjonsson T, Ronnov-Jessen L, Villadsen R, Rank F, Bissell MJ, Petersen OW. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition. J Cell Sci. 2002;115(Pt 1):39–50.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Radice GL, Ferreira-Cornwell MC, Robinson SD, Rayburn H, Chodosh LA, Takeichi M, et al. Precocious mammary gland development in P-cadherin-deficient mice. J Cell Biol. 1997;139(4):1025–32.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Faraldo MM, Teuliere J, Deugnier MA, Taddei-De La Hosseraye I, Thiery JP, Glukhova MA. Myoepithelial cells in the control of mammary development and tumorigenesis: data from genetically modified mice. J Mammary Gland Biol Neoplasia. 2005;10(3):211–9.Google Scholar
  53. 53.
    Adriance MC, Inman JL, Petersen OW, Bissell MJ. Myoepithelial cells: good fences make good neighbors. Breast Cancer Res. 2005;7(5):190–7.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    El-Sabban ME, Abi-Mosleh LF, Talhouk RS. Developmental regulation of gap junctions and their role in mammary epithelial cell differentiation. J Mammary Gland Biol Neoplasia. 2003;8(4):463–73.PubMedCrossRefGoogle Scholar
  55. 55.
    Gudjonsson T, Adriance MC, Sternlicht MD, Petersen OW, Bissell MJ. Myoepithelial cells: their origin and function in breast morphogenesis and neoplasia. J Mammary Gland Biol Neoplasia. 2005;10(3):261–72.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Lakhani SR, O’Hare MJ. The mammary myoepithelial cell–Cinderella or ugly sister? Breast Cancer Res. 2001;3(1):1–4.Google Scholar
  57. 57.
    Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66(12):6063–71.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Hennighausen L, Robinson GW. Information networks in the mammary gland. Nat Rev. 2005;6(9):715–25.CrossRefGoogle Scholar
  59. 59.
    Savarese TM, Low HP, Baik I, Strohsnitter WC, Hsieh CC. Normal breast stem cells, malignant breast stem cells, and the perinatal origin of breast cancer. Stem cell reviews. 2006;2(2):103–10.PubMedCrossRefGoogle Scholar
  60. 60.
    Smalley M, Ashworth A. Stem cells and breast cancer: a field in transit. Nat Rev Cancer. 2003;3(11):832–44.PubMedCrossRefGoogle Scholar
  61. 61.
    Chepko G, Smith GH. Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell. 1997;29(2):239–53.PubMedCrossRefGoogle Scholar
  62. 62.
    Smith GH, Medina D. A morphologically distinct candidate for an epithelial stem cell in mouse mammary gland. J Cell Sci. 1988;90(Pt 1):173–83.PubMedGoogle Scholar
  63. 63.
    Smith GH, Strickland P, Daniel CW. Putative epithelial stem cell loss corresponds with mammary growth senescence. Cell Tissue Res. 2002;310(3):313–20.PubMedCrossRefGoogle Scholar
  64. 64.
    Daniel CW, De Ome KB, Young JT, Blair PB, Faulkin LJ Jr. The in vivo life span of normal and preneoplastic mouse mammary glands: a serial transplantation study. Proc Natl Acad Sci USA. 1968;61(1):53–60.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Kordon EC, Smith GH. An entire functional mammary gland may comprise the progeny from a single cell. Development. 1998;125(10):1921–30.Google Scholar
  66. 66.
    Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439(7072):84–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Stingl J, Eaves CJ, Kuusk U, Emerman JT. Phenotypic and functional characterization in vitro of a multipotent epithelial cell present in the normal adult human breast. Differentiation (research in biological diversity). 1998;63(4):201–13.CrossRefGoogle Scholar
  68. 68.
    Villadsen R, Fridriksdottir AJ, Ronnov-Jessen L, Gudjonsson T, Rank F, LaBarge MA, et al. Evidence for a stem cell hierarchy in the adult human breast. J Cell Biol. 2007;177(1):87–101.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Florek M, Haase M, Marzesco AM, Freund D, Ehninger G, Huttner WB, et al. Prominin-1/CD133, a neural and hematopoietic stem cell marker, is expressed in adult human differentiated cells and certain types of kidney cancer. Cell Tissue Res. 2005;319(1):15–26 Epub 2004/11/24.PubMedCrossRefGoogle Scholar
  70. 70.
    Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA. Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol. 2002;245(1):42–56.PubMedCrossRefGoogle Scholar
  71. 71.
    Rios AC, Fu NY, Lindeman GJ, Visvader JE. In situ identification of bipotent stem cells in the mammary gland. Nature. 2014;506(7488):322–7 Epub 2014/01/28.PubMedCrossRefGoogle Scholar
  72. 72.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100(7):3983–8 Epub 2003/03/12.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Ginestier C, Wicha MS. Mammary stem cell number as a determinate of breast cancer risk. Breast Cancer Res. 2007;9(4):109.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Storci G, Sansone P, Trere D, Tavolari S, Taffurelli M, Ceccarelli C, et al. The basal-like breast carcinoma phenotype is regulated by SLUG gene expression. J Pathol. 2008;214(1):25–37 Epub 2007/11/02.PubMedCrossRefGoogle Scholar
  75. 75.
    Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski L. Brca1 breast tumors contain distinct CD44 +/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res. 2008;10(1):R10. Epub 2008/02/05.Google Scholar
  76. 76.
    Liu TJ, Sun BC, Zhao XL, Zhao XM, Sun T, Gu Q, et al. CD133+ cells with cancer stem cell characteristics associates with vasculogenic mimicry in triple-negative breast cancer. Oncogene. 2013;32(5):544–53 Epub 2012/04/04.PubMedCrossRefGoogle Scholar
  77. 77.
    Clarke RB. Isolation and characterization of human mammary stem cells. Cell Prolif. 2005;38(6):375–86.PubMedCrossRefGoogle Scholar
  78. 78.
    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 USA. 2006;103(7):2196–201.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    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 USA. 2010;107(7):2989–94 Epub 2010/02/06.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Matulka LA, Triplett AA, Wagner KU. Parity-induced mammary epithelial cells are multipotent and express cell surface markers associated with stem cells. Dev Biol. 2007;303(1):29–44.PubMedCrossRefGoogle Scholar
  81. 81.
    Chang TH, Kunasegaran K, Tarulli GA, De Silva D, Voorhoeve PM, Pietersen AM. New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res. 2014;16(1):R1. Epub 2014/01/09.Google Scholar
  82. 82.
    Russo J, Balogh GA, Chen J, Fernandez SV, Fernbaugh R, Heulings R, et al. The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention. Front Biosci. 2006;11:151–72.PubMedCrossRefGoogle Scholar
  83. 83.
    Stingl J, Raouf A, Emerman JT, Eaves CJ. Epithelial progenitors in the normal human mammary gland. J Mammary Gland Biol Neoplasia. 2005;10(1):49–59.PubMedCrossRefGoogle Scholar
  84. 84.
    Wagner KU, Smith GH. Pregnancy and stem cell behavior. J Mammary Gland Biol Neoplasia. 2005;10(1):25–36.PubMedCrossRefGoogle Scholar
  85. 85.
    Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003;17(10):1253–70.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Liu S, Dontu G, Wicha MS. Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res. 2005;7(3):86–95.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Kouros-Mehr H, Werb Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn. 2006;235(12):3404–12 Epub 2006/10/14.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Incassati A, Chandramouli A, Eelkema R, Cowin P. Key signaling nodes in mammary gland development and cancer: beta-catenin. Breast Cancer Res. 2010;12(6):213. Epub 2010/11/12.Google Scholar
  89. 89.
    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 Epub 2010/05/07.PubMedCrossRefGoogle Scholar
  90. 90.
    Asselin-Labat ML, Vaillant F, Sheridan JM, Pal B, Wu D, Simpson ER, et al. Control of mammary stem cell function by steroid hormone signalling. Nature. 2010;465(7299):798–802 Epub 2010/04/13.PubMedCrossRefGoogle Scholar
  91. 91.
    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 Epub 2010/10/01.PubMedCrossRefGoogle Scholar
  92. 92.
    Gu B, Watanabe K, Sun P, Fallahi M, Dai X. Chromatin effector Pygo2 mediates Wnt-notch crosstalk to suppress luminal/alveolar potential of mammary stem and basal cells. Cell Stem Cell. 2013;13(1):48–61 Epub 2013/05/21.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Lafkas D, Rodilla V, Huyghe M, Mourao L, Kiaris H, Fre S. Notch3 marks clonogenic mammary luminal progenitor cells in vivo. J Cell Biol. 2013;203(1):47–56 Epub 2013/10/09.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Andrechek ER, White D, Muller WJ. Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth. Oncogene. 2005;24(5):932–7 Epub 2004/12/08.PubMedCrossRefGoogle Scholar
  95. 95.
    Jackson-Fisher AJ, Bellinger G, Ramabhadran R, Morris JK, Lee KF, Stern DF. ErbB2 is required for ductal morphogenesis of the mammary gland. Proc Natl Acad Sci USA. 2004;101(49):17138–43 Epub 2004/12/01.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27(47):6120–30 Epub 2008/07/02.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Paik S, Kim C, Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med. 2008;358(13):1409–11 Epub 2008/03/28.PubMedCrossRefGoogle Scholar
  98. 98.
    Perez EA, Reinholz MM, Hillman DW, Tenner KS, Schroeder MJ, Davidson NE, et al. HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol. 2010;28(28):4307–15.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk. Lancet Oncol. 2002;3(9):565–74 Epub 2002/09/10.PubMedCrossRefGoogle Scholar
  100. 100.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–38 Epub 2003/04/25.PubMedCrossRefGoogle Scholar
  101. 101.
    Kleinberg DL, Feldman M, Ruan W. IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis. J Mammary Gland Biol Neoplasia. 2000;5(1):7–17.PubMedCrossRefGoogle Scholar
  102. 102.
    Kleinberg DL, Ruan W. IGF-I, GH, and sex steroid effects in normal mammary gland development. J Mammary Gland Biol Neoplasia. 2008;13(4):353–60 Epub 2008/11/27.PubMedCrossRefGoogle Scholar
  103. 103.
    Tamimi RM, Colditz GA, Wang Y, Collins LC, Hu R, Rosner B, et al. Expression of IGF1R in normal breast tissue and subsequent risk of breast cancer. Breast Cancer Res Treat. 2011;128(1):243–50 Epub 2011/01/05.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Esper RM, Dame M, McClintock S, Holt PR, Dannenberg AJ, Wicha MS, et al. Leptin and adiponectin modulate the self-renewal of normal human breast epithelial stem cells. Cancer Prev Res (Phila). 2015;8(12):1174–83 Epub 2015/10/22.CrossRefGoogle Scholar
  105. 105.
    Huh SJ, Oh H, Peterson MA, Almendro V, Hu R, Bowden M, et al. The proliferative activity of mammary epithelial cells in normal tissue predicts breast cancer risk in premenopausal women. Cancer Res. 2016;76(7):1926–34 Epub 2016/03/05.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Guelstein VI, Tchypysheva TA, Ermilova VD, Ljubimov AV. Myoepithelial and basement membrane antigens in benign and malignant human breast tumors. Int J Cancer. 1993;53(2):269–77.PubMedCrossRefGoogle Scholar
  107. 107.
    Prince JM, Klinowska TC, Marshman E, Lowe ET, Mayer U, Miner J, et al. Cell-matrix interactions during development and apoptosis of the mouse mammary gland in vivo. Dev Dyn. 2002;223(4):497–516.PubMedCrossRefGoogle Scholar
  108. 108.
    Woodward TL, Mienaltowski AS, Modi RR, Bennett JM, Haslam SZ. Fibronectin and the alpha(5)beta(1) integrin are under developmental and ovarian steroid regulation in the normal mouse mammary gland. Endocrinology. 2001;142(7):3214–22.Google Scholar
  109. 109.
    Streuli CH, Bissell MJ. Expression of extracellular matrix components is regulated by substratum. J Cell Biol. 1990;110(4):1405–15.PubMedCrossRefGoogle Scholar
  110. 110.
    Pullan S, Wilson J, Metcalfe A, Edwards GM, Goberdhan N, Tilly J, et al. Requirement of basement membrane for the suppression of programmed cell death in mammary epithelium. J Cell Sci. 1996;109(Pt 3):631–42.PubMedGoogle Scholar
  111. 111.
    Streuli C. Extracellular matrix remodelling and cellular differentiation. Curr Opin Cell Biol. 1999;11(5):634–40.PubMedCrossRefGoogle Scholar
  112. 112.
    Novaro V, Roskelley CD, Bissell MJ. Collagen-IV and laminin-1 regulate estrogen receptor alpha expression and function in mouse mammary epithelial cells. J Cell Sci. 2003;116(Pt 14):2975–86.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Weir ML, Oppizzi ML, Henry MD, Onishi A, Campbell KP, Bissell MJ, et al. Dystroglycan loss disrupts polarity and beta-casein induction in mammary epithelial cells by perturbing laminin anchoring. J Cell Sci. 2006;119(Pt 19):4047–58.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Streuli CH, Schmidhauser C, Bailey N, Yurchenco P, Skubitz AP, Roskelley C, et al. Laminin mediates tissue-specific gene expression in mammary epithelia. J Cell Biol. 1995;129(3):591–603.PubMedCrossRefGoogle Scholar
  115. 115.
    Farrelly N, Lee YJ, Oliver J, Dive C, Streuli CH. Extracellular matrix regulates apoptosis in mammary epithelium through a control on insulin signaling. J Cell Biol. 1999;144(6):1337–48.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Pujuguet P, Simian M, Liaw J, Timpl R, Werb Z, Bissell MJ. Nidogen-1 regulates laminin-1-dependent mammary-specific gene expression. J Cell Sci. 2000;113(Pt 5):849–58.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Streuli CH, Edwards GM. Control of normal mammary epithelial phenotype by integrins. J Mammary Gland Biol Neoplasia. 1998;3(2):151–63.PubMedCrossRefGoogle Scholar
  118. 118.
    Li N, Zhang Y, Naylor MJ, Schatzmann F, Maurer F, Wintermantel T, et al. Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli. EMBO J. 2005;24(11):1942–53.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Klinowska TC, Soriano JV, Edwards GM, Oliver JM, Valentijn AJ, Montesano R, et al. Laminin and beta1 integrins are crucial for normal mammary gland development in the mouse. Dev Biol. 1999;215(1):13–32.PubMedCrossRefGoogle Scholar
  120. 120.
    Naylor MJ, Li N, Cheung J, Lowe ET, Lambert E, Marlow R, et al. Ablation of beta1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation. J Cell Biol. 2005;171(4):717–28.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Barcellos-Hoff MH, Aggeler J, Ram TG, Bissell MJ. Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. Development. 1989;105(2):223–35.Google Scholar
  122. 122.
    Blatchford DR, Quarrie LH, Tonner E, McCarthy C, Flint DJ, Wilde CJ. Influence of microenvironment on mammary epithelial cell survival in primary culture. J Cell Physiol. 1999;181(2):304–11.PubMedCrossRefGoogle Scholar
  123. 123.
    Neville MC. Lactation and its hormonal control. In: Neill JD, editor. Knobil and Neill’s physiology of reproduction. 3rd ed. Amsterdam: Elsevier; 2006. p. 2993–3054.Google Scholar
  124. 124.
    Eyden BP, Watson RJ, Harris M, Howell A. Intralobular stromal fibroblasts in the resting human mammary gland: ultrastructural properties and intercellular relationships. J Submicrosc Cytol. 1986;18(2):397–408.PubMedGoogle Scholar
  125. 125.
    Atherton AJ, Monaghan P, Warburton MJ, Robertson D, Kenny AJ, Gusterson BA. Dipeptidyl peptidase IV expression identifies a functional sub-population of breast fibroblasts. Int J Cancer. 1992;50(1):15–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Sadlonova A, Novak Z, Johnson MR, Bowe DB, Gault SR, Page GP, et al. Breast fibroblasts modulate epithelial cell proliferation in three-dimensional in vitro co-culture. Breast Cancer Res. 2005;7(1):R46–59.PubMedCrossRefGoogle Scholar
  127. 127.
    Parmar H, Cunha GR. Epithelial-stromal interactions in the mouse and human mammary gland in vivo. Endocr Relat Cancer. 2004;11(3):437–58.PubMedCrossRefGoogle Scholar
  128. 128.
    Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 2002;4(4):155–64.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Schwertfeger KL, Rosen JM, Cohen DA. Mammary gland macrophages: pleiotropic functions in mammary development. J Mammary Gland Biol Neoplasia. 2006;11(3–4):229–38.PubMedCrossRefGoogle Scholar
  130. 130.
    Monks J, Geske FJ, Lehman L, Fadok VA. Do inflammatory cells participate in mammary gland involution? J Mammary Gland Biol Neoplasia. 2002;7(2):163–76.Google Scholar
  131. 131.
    Sternlicht MD. Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis. Breast Cancer Res. 2006;8(1):201.PubMedCrossRefGoogle Scholar
  132. 132.
    Nishimura T. Expression of potential lymphocyte trafficking mediator molecules in the mammary gland. Vet Res. 2003;34(1):3–10.PubMedCrossRefGoogle Scholar
  133. 133.
    Dabiri S, Huntsman D, Makretsov N, Cheang M, Gilks B, Bajdik C, et al. The presence of stromal mast cells identifies a subset of invasive breast cancers with a favorable prognosis. Mod Pathol. 2004;17(6):690–5.PubMedCrossRefGoogle Scholar
  134. 134.
    Hartveit F. Mast cell association with collagen fibres in human breast stroma. Eur J Morphol. 1993;31(3):209–18.PubMedGoogle Scholar
  135. 135.
    Popescu LM, Andrei F, Hinescu ME. Snapshots of mammary gland interstitial cells: methylene-blue vital staining and c-kit immunopositivity. J Cell Mol Med. 2005;9(2):476–7.PubMedCrossRefGoogle Scholar
  136. 136.
    Popescu LM, Gherghiceanu M, Cretoiu D, Radu E. The connective connection: interstitial cells of Cajal (ICC) and ICC-like cells establish synapses with immunoreactive cells. Electron microscope study in situ. J Cell Mol Med. 2005;9(3):714–30.PubMedCrossRefGoogle Scholar
  137. 137.
    Radu E, Regalia T, Ceafalan L, Andrei F, Cretoiu D, Popescu LM. Cajal-type cells from human mammary gland stroma: phenotype characteristics in cell culture. J Cell Mol Med. 2005;9(3):748–52.PubMedCrossRefGoogle Scholar
  138. 138.
    Gherghiceanu M, Popescu LM. Interstitial Cajal-like cells (ICLC) in human resting mammary gland stroma. Transmission electron microscope (TEM) identification. J Cell Mol Med. 2005;9(4):893–910.PubMedCrossRefGoogle Scholar
  139. 139.
    Haslam SZ, Woodward TL. Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland. Breast Cancer Res. 2003;5(4):208–15.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110(6):673–87.PubMedCrossRefGoogle Scholar
  141. 141.
    Schatzmann F, Marlow R, Streuli CH. Integrin signaling and mammary cell function. J Mammary Gland Biol Neoplasia. 2003;8(4):395–408.PubMedCrossRefGoogle Scholar
  142. 142.
    Alowami S, Troup S, Al-Haddad S, Kirkpatrick I, Watson PH. Mammographic density is related to stroma and stromal proteoglycan expression. Breast Cancer Res. 2003;5(5):R129–35.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Delehedde M, Lyon M, Sergeant N, Rahmoune H, Fernig DG. Proteoglycans: pericellular and cell surface multireceptors that integrate external stimuli in the mammary gland. J Mammary Gland Biol Neoplasia. 2001;6(3):253–73.PubMedCrossRefGoogle Scholar
  144. 144.
    Silverman AJ, Livne I, Witkin JW. The gonadotropin-releasing hormone (GnRH), neuronal systems: immunocytochemistry and in situ hybridisation. In: Knobil E, Neill JD, editors. Physiol Reprod. New York: Raven Press Ltd.; 1994. p. 1683–709.Google Scholar
  145. 145.
    Guyton AJ. Textbook of medical hysiology. 11th ed. ‎Philadelphia: Elsevier Saunders.Google Scholar
  146. 146.
    Seagroves TN, Hadsell D, McManaman J, Palmer C, Liao D, McNulty W, et al. HIF1alpha is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland. Development. 2003;130(8):1713–24.Google Scholar
  147. 147.
    Speirs V, Skliris GP, Burdall SE, Carder PJ. Distinct expression patterns of ER alpha and ER beta in normal human mammary gland. J Clin Pathol. 2002;55(5):371–4.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Levin ER. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol. 2005;19(8):1951–9.Google Scholar
  149. 149.
    Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M. Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways. Mol Cell Biol. 2004;24(17):7681–94.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Clarke RB, Howell A, Potten CS, Anderson E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res. 1997;57(22):4987–91.PubMedGoogle Scholar
  151. 151.
    Howell A. Pure oestrogen antagonists for the treatment of advanced breast cancer. Endocr Relat Cancer. 2006;13(3):689–706.PubMedCrossRefGoogle Scholar
  152. 152.
    Hall JM, McDonnell DP. The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology. 1999;140(12):5566–78.Google Scholar
  153. 153.
    Asselin-Labat ML, Shackleton M, Stingl J, Vaillant F, Forrest NC, Eaves CJ, et al. Steroid hormone receptor status of mouse mammary stem cells. J Natl Cancer Inst. 2006;98(14):1011–4.PubMedCrossRefGoogle Scholar
  154. 154.
    Sleeman KE, Kendrick H, Robertson D, Isacke CM, Ashworth A, Smalley MJ. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. J Cell Biol. 2007;176(1):19–26.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Clarke RB. Ovarian steroids and the human breast: regulation of stem cells and cell proliferation. Maturitas. 2006;54(4):327–34.PubMedCrossRefGoogle Scholar
  156. 156.
    Cheng G, Weihua Z, Warner M, Gustafsson JA. Estrogen receptors ER alpha and ER beta in proliferation in the rodent mammary gland. Proc Natl Acad Sci USA. 2004;101(11):3739–46.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Khan SA, Bhandare D, Chatterton RT Jr. The local hormonal environment and related biomarkers in the normal breast. Endocr Relat Cancer. 2005;12(3):497–510.PubMedCrossRefGoogle Scholar
  158. 158.
    Forster C, Makela S, Warri A, Kietz S, Becker D, Hultenby K, et al. Involvement of estrogen receptor beta in terminal differentiation of mammary gland epithelium. Proc Natl Acad Sci USA. 2002;99(24):15578–83.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Seagroves TN, Rosen JM. Control of mammary epithelial cell proliferation: the unique role of the progesterone receptor. In: Burnstein K, editor. Sex hormones and cell cycle regulation: Alphen aan den Rijn: Kluwer Press; 2002. p. 33–55.Google Scholar
  160. 160.
    Conneely OM, Jericevic BM, Lydon JP. Progesterone receptors in mammary gland development and tumorigenesis. J Mammary Gland Biol Neoplasia. 2003;8(2):205–14.PubMedCrossRefGoogle Scholar
  161. 161.
    Leonhardt SA, Boonyaratanakornkit V, Edwards DP. Progesterone receptor transcription and non-transcription signaling mechanisms. Steroids. 2003;68(10–13):761–70.PubMedCrossRefGoogle Scholar
  162. 162.
    Aupperlee MD, Haslam SZ. Differential hormonal regulation and function of progesterone receptor isoforms in normal adult mouse mammary gland. Endocrinology. 2007;148(5):2290–300.PubMedCrossRefGoogle Scholar
  163. 163.
    Lydon JP, Sivaraman L, Conneely OM. A reappraisal of progesterone action in the mammary gland. J Mammary Gland Biol Neoplasia. 2000;5(3):325–38.PubMedCrossRefGoogle Scholar
  164. 164.
    Cunha GR, Young P, Hom YK, Cooke PS, Taylor JA, Lubahn DB. Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombinants. J Mammary Gland Biol Neoplasia. 1997;2(4):393–402.PubMedCrossRefGoogle Scholar
  165. 165.
    Brisken C, Rajaram RD. Alveolar and lactogenic differentiation. J Mammary Gland Biol Neoplasia. 2006;11(3–4):239–48.PubMedCrossRefGoogle Scholar
  166. 166.
    Yang Y, Spitzer E, Meyer D, Sachs M, Niemann C, Hartmann G, et al. Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland. J Cell Biol. 1995;131(1):215–26.PubMedCrossRefGoogle Scholar
  167. 167.
    Kariagina A, Aupperlee MD, Haslam SZ. Progesterone receptor isoforms and proliferation in the rat mammary gland during development. Endocrinology. 2007;148(6):2723–36.PubMedCrossRefGoogle Scholar
  168. 168.
    Eigeliene N, Harkonen P, Erkkola R. Effects of estradiol and medroxyprogesterone acetate on morphology, proliferation and apoptosis of human breast tissue in organ cultures. BMC Cancer. 2006;6:246.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev. 2000;80(4):1523–631.PubMedGoogle Scholar
  170. 170.
    Horseman ND. Prolactin and mammary gland development. J Mammary Gland Biol Neoplasia. 1999;4(1):79–88.PubMedCrossRefGoogle Scholar
  171. 171.
    Dong J, Tsai-Morris CH, Dufau ML. A novel estradiol/estrogen receptor alpha-dependent transcriptional mechanism controls expression of the human prolactin receptor. J Biol Chem. 2006;281(27):18825–36.PubMedCrossRefGoogle Scholar
  172. 172.
    Miyoshi K, Shillingford JM, Smith GH, Grimm SL, Wagner KU, Oka T, et al. Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium. J Cell Biol. 2001;155(4):531–42 Epub 2001/11/14.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Cui Y, Riedlinger G, Miyoshi K, Tang W, Li C, Deng CX, et al. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol. 2004;24(18):8037–47 Epub 2004/09/02.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Yamaji D, Na R, Feuermann Y, Pechhold S, Chen W, Robinson GW, et al. Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A. Genes Dev. 2009;23(20):2382–7 Epub 2009/10/17.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol. 2007;9(2):201–9.PubMedCrossRefGoogle Scholar
  176. 176.
    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):1041–55.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    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 Epub 1999/10/16.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Kritikou EA, Sharkey A, Abell K, Came PJ, Anderson E, Clarkson RW, et al. A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland. Development. 2003;130(15):3459–68. Epub 2003/06/18.Google Scholar
  179. 179.
    Nguyen AV, Pollard JW. Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution. Development. 2000;127(14):3107–18. Epub 2000/06/23.Google Scholar
  180. 180.
    Tiffen PG, Omidvar N, Marquez-Almuina N, Croston D, Watson CJ, Clarkson RW. A dual role for oncostatin M signaling in the differentiation and death of mammary epithelial cells in vivo. Molecular endocrinology. 2008;22(12):2677–88. Epub 2008/10/18.Google Scholar
  181. 181.
    Honda K, Kazumi N, Murata T, Higuchi T. Prolactin releasing peptides modulate background firing rate and milk-ejection related burst of oxytocin cells in the supraoptic nucleus. Brain Res Bull. 2004;63:315–9.PubMedCrossRefGoogle Scholar
  182. 182.
    Bussolati G, Cassoni P, Ghisolfi G, Negro F, Sapino A. Immunolocalization and gene expression of oxytocin receptors in carcinomas and non-neoplastic tissues of the breast. Am J Pathol. 1996;148(6):1895–903.PubMedPubMedCentralGoogle Scholar
  183. 183.
    Reversi A, Cassoni P, Chini B. Oxytocin receptor signaling in myoepithelial and cancer cells. J Mammary Gland Biol Neoplasia. 2005;10(3):221–9.PubMedCrossRefGoogle Scholar
  184. 184.
    Labrie F. Dehydroepiandrosterone, androgens and the mammary gland. Gynecol Endocrinol. 2006;22(3):118–30.PubMedCrossRefGoogle Scholar
  185. 185.
    Wilson CL, Sims AH, Howell A, Miller CJ, Clarke RB. Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue. Endocr Relat Cancer. 2006;13(2):617–28.PubMedCrossRefGoogle Scholar
  186. 186.
    Woodward TL, Xie JW, Haslam SZ. The role of mammary stroma in modulating the proliferative response to ovarian hormones in the normal mammary gland. J Mammary Gland Biol Neoplasia. 1998;3(2):117–31.PubMedCrossRefGoogle Scholar
  187. 187.
    Lamarca HL, Rosen JM. Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage. Breast Cancer Res. 2007;9(4):304.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Zhang HZ, Bennett JM, Smith KT, Sunil N, Haslam SZ. Estrogen mediates mammary epithelial cell proliferation in serum-free culture indirectly via mammary stroma-derived hepatocyte growth factor. Endocrinology. 2002;143(9):3427–34.PubMedCrossRefGoogle Scholar
  189. 189.
    Soriano JV, Pepper MS, Orci L, Montesano R. Roles of hepatocyte growth factor/scatter factor and transforming growth factor-beta1 in mammary gland ductal morphogenesis. J Mammary Gland Biol Neoplasia. 1998;3(2):133–50.PubMedCrossRefGoogle Scholar
  190. 190.
    Pollard JW. Tumour-stromal interactions. Transforming growth factor-beta isoforms and hepatocyte growth factor/scatter factor in mammary gland ductal morphogenesis. Breast Cancer Res. 2001;3(4):230–7.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Kamalati T, Niranjan B, Yant J, Buluwela L. HGF/SF in mammary epithelial growth and morphogenesis: in vitro and in vivo models. J Mammary Gland Biol Neoplasia. 1999;4(1):69–77.PubMedCrossRefGoogle Scholar
  192. 192.
    Cohen S. EGF and its receptor: historical perspective. Introduction. J Mammary Gland Biol Neoplasia. 1997;2(2):93–6.PubMedCrossRefGoogle Scholar
  193. 193.
    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.Google Scholar
  194. 194.
    Osin PP, Anbazhagan R, Bartkova J, Nathan B, Gusterson BA. Breast development gives insights into breast disease. Histopathology. 1998;33(3):275–83.PubMedCrossRefGoogle Scholar
  195. 195.
    Ruan W, Kleinberg DL. Insulin-like growth factor I is essential for terminal end bud formation and ductal morphogenesis during mammary development. Endocrinology. 1999;140(11):5075–81.Google Scholar
  196. 196.
    Wood TL, Yee D. Introduction: IGFs and IGFBPs in the normal mammary gland and in breast cancer. J Mammary Gland Biol Neoplasia. 2000;5(1):1–5.PubMedCrossRefGoogle Scholar
  197. 197.
    Ahmad T, Farnie G, Bundred NJ, Anderson NG. The mitogenic action of insulin-like growth factor I in normal human mammary epithelial cells requires the epidermal growth factor receptor tyrosine kinase. J Biol Chem. 2004;279(3):1713–9.PubMedCrossRefGoogle Scholar
  198. 198.
    Wang W, Morrison B, Galbaugh T, Jose CC, Kenney N, Cutler ML. Glucocorticoid induced expression of connective tissue growth factor contributes to lactogenic differentiation of mouse mammary epithelial cells. J Cell Physiol. 2008;214(1):38–46.PubMedCrossRefGoogle Scholar
  199. 199.
    Jiang WG, Watkins G, Fodstad O, Douglas-Jones A, Mokbel K, Mansel RE. Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer. Endocr Relat Cancer. 2004;11(4):781–91.PubMedCrossRefGoogle Scholar
  200. 200.
    Anbazhagan R, Gusterson BA. Prenatal factors may influence predisposition to breast cancer. Eur J Cancer. 1994;30A(1):1–3.PubMedCrossRefGoogle Scholar
  201. 201.
    Hilakivi-Clarke L, de Assis S. Fetal origins of breast cancer. Trends Endocrinol Metab: TEM. 2006;17(9):340–8.PubMedCrossRefGoogle Scholar
  202. 202.
    Trichopoulos D, Lagiou P, Adami HO. Towards an integrated model for breast cancer etiology: the crucial role of the number of mammary tissue-specific stem cells. Breast Cancer Res. 2005;7(1):13–7.PubMedCrossRefGoogle Scholar
  203. 203.
    Hens JR, Wysolmerski JJ. Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland. Breast Cancer Res. 2005;7(5):220–4.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Jolicoeur F. Intrauterine breast development and the mammary myoepithelial lineage. J Mammary Gland Biol Neoplasia. 2005;10(3):199–210.PubMedCrossRefGoogle Scholar
  205. 205.
    Arey L. Developmental anatomy: a textbook adn laboratory manual of embryology. Revised 7th ed. Philadelphia: W. B. Saunders; 1974.Google Scholar
  206. 206.
    Russo J, Russo IH. Mammary gland development. In: Knobil E, Neill, JD, editors. Encyclopedia of reproduction; 1999.Google Scholar
  207. 207.
    Sadler TW. Langman’s medical embryolgy. 9th ed. Baltimore: Lippincott Williams & Wilkins; 2003.Google Scholar
  208. 208.
    Robinson GW, Karpf AB, Kratochwil K. Regulation of mammary gland development by tissue interaction. J Mammary Gland Biol Neoplasia. 1999;4(1):9–19.PubMedCrossRefGoogle Scholar
  209. 209.
    Anbazhagan R, Osin PP, Bartkova J, Nathan B, Lane EB, Gusterson BA. The development of epithelial phenotypes in the human fetal and infant breast. J Pathol. 1998;184(2):197–206.PubMedCrossRefGoogle Scholar
  210. 210.
    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.PubMedCrossRefGoogle Scholar
  211. 211.
    Tobon H, Slazar H. Ultrastructure of the human mammary gland. I. Development of the fetal gland throughout gestation. J Clin Endocrinol Metab. 1974;39(3):443–56.PubMedCrossRefGoogle Scholar
  212. 212.
    Kratochwil K, Schwartz P. Tissue interaction in androgen response of embryonic mammary rudiment of mouse: identification of target tissue for testosterone. Proc Natl Acad Sci USA. 1976;73(11):4041–4.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Turner CW. The anatomy of the mammary gland in cattle. II. Fetal development. Missouri Agric Exp Sta Res Bull. 1930;160:5–39.Google Scholar
  214. 214.
    Bocchinfuso WP, Lindzey JK, Hewitt SC, Clark JA, Myers PH, Cooper R, et al. Induction of mammary gland development in estrogen receptor-alpha knockout mice. Endocrinology. 2000;141(8):2982–94.Google Scholar
  215. 215.
    Aubert MJ, Grumbach MM, Kaplan SL. The ontogenesis of human fetal hormones. III. Prolactin. J Clin Investig. 1975;56(1):155–64.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Keeling JW, Ozer E, King G, Walker F. Oestrogen receptor alpha in female fetal, infant, and child mammary tissue. J Pathol. 2000;191(4):449–51.PubMedCrossRefGoogle Scholar
  217. 217.
    Naccarato AG, Viacava P, Vignati S, Fanelli G, Bonadio AG, Montruccoli G, et al. Bio-morphological events in the development of the human female mammary gland from fetal age to puberty. Virchows Arch. 2000;436(5):431–8.PubMedCrossRefGoogle Scholar
  218. 218.
    Nathan B, Anbazhagan R, Clarkson P, Bartkova J. Expression of BCL-2 in the developing human fetal and infant breast. Histopathology. 1994;24:73–6.PubMedCrossRefGoogle Scholar
  219. 219.
    Magdinier F, Dalla Venezia N, Lenoir GM, Frappart L, Dante R. BRCA1 expression during prenatal development of the human mammary gland. Oncogene. 1999;18(27):4039–43.Google Scholar
  220. 220.
    Casey TM, Mulvey TM, Patnode TA, Dean A, Zakrzewska E, Plaut K. Mammary epithelial cells treated concurrently with TGF-alpha and TGF-beta exhibit enhanced proliferation and death. Exp Biol Med. 2007;232(8):1027–40.Google Scholar
  221. 221.
    Stull MA, Rowzee AM, Loladze AV, Wood TL. Growth factor regulation of cell cycle progression in mammary epithelial cells. J Mammary Gland Biol Neoplasia. 2004;9(1):15–26.PubMedCrossRefGoogle Scholar
  222. 222.
    Streuli CH, Schmidhauser C, Kobrin M, Bissell MJ, Derynck R. Extracellular matrix regulates expression of the TGF-beta 1 gene. J Cell Biol. 1993;120(1):253–60.PubMedCrossRefGoogle Scholar
  223. 223.
    Chammas R, Taverna D, Cella N, Santos C, Hynes NE. Laminin and tenascin assembly and expression regulate HC11 mouse mammary cell differentiation. J Cell Sci. 1994;107(Pt 4):1031–40.PubMedGoogle Scholar
  224. 224.
    Dunbar ME, Wysolmerski JJ. The role of parathyroid hormone-related protein (PTHrP) in mammary development, lactation, and breast cancer. 1996; Available from:
  225. 225.
    McKiernan J, Coyne J, Cahalane S. Histology of breast development in early life. Arch Dis Child. 1988;63(2):136–9.PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    McKiernan JF, Hull D. Breast development in the newborn. Arch Dis Child. 1981;56:525–9.PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Russo J, Russo IH. Toward a physiological approach to breast cancer prevention. Cancer Epidemiol Biomark Prev. 1994;3(4):353–64.Google Scholar
  228. 228.
    Russo J, Russ IH. Development of the human mammary gland. In: Neville MD, Daniel C, editors. The mammary gland: development, regulation and function. New York: Plenum Press; 1987.Google Scholar
  229. 229.
    McKiernan JF, Hull D. Prolactin, maternal oestrogens, and breast development in the newborn. Arch Dis Child. 1981;56(10):770–4.PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Schmidt IM, Chellarkooty M, Haavisto A, Boisen KA, Damgaard IN, Steendahl U, et al. Gender difference in breast tissue size in infancy: correlation with serum estradiol. Pediatr Res. 2002;52(5):682–6.PubMedCrossRefGoogle Scholar
  231. 231.
    Pierce DF Jr, Johnson MD, Matsui Y, Robinson SD, Gold LI, Purchio AF, et al. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1. Genes Dev. 1993;7(12A):2308–17.PubMedCrossRefGoogle Scholar
  232. 232.
    Russo I, Medado J, Russo J. Endocrine influences on the mammary gland. In: Jones T, Mohr U, Hunt E, editors. Integument and mammary glands. Berlin: Springer; 1989.Google Scholar
  233. 233.
    Humphreys RC. Programmed cell death in the terminal endbud. J Mammary Gland Biol Neoplasia. 1999;4(2):213–20.PubMedCrossRefGoogle Scholar
  234. 234.
    Humphreys RC, Krajewska M, Krnacik S, Jaeger R, Weiher H, Krajewski S, et al. Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis. Development. 1996;122(12):4013–22.Google Scholar
  235. 235.
    Britt K, Ashworth A, Smalley M. Pregnancy and the risk of breast cancer. Endocr Relat Cancer. 2007;14(4):907–33.PubMedCrossRefGoogle Scholar
  236. 236.
    Williams JM, Daniel CW. Mammary ductal elongation: differentiation of myoepithelium and basal lamina during branching morphogenesis. Dev Biol. 1983;97(2):274–90.PubMedCrossRefGoogle Scholar
  237. 237.
    Topper YJ, Freeman CS. Multiple hormone interactions in the developmental biology of the mammary gland. Physiol Rev. 1980;60(4):1049–106.PubMedGoogle Scholar
  238. 238.
    Anderson E, Clarke RB, Howell A. Estrogen responsiveness and control of normal human breast proliferation. J Mammary Gland Biol Neoplasia. 1998;3(1):23–35.PubMedCrossRefGoogle Scholar
  239. 239.
    Laurence DJ, Monaghan P, Gusterson BA. The development of the normal human breast. Oxf Rev Reprod Biol. 1991;13:149–74.PubMedGoogle Scholar
  240. 240.
    Russo J, Hu YF, Silva ID, Russo IH. Cancer risk related to mammary gland structure and development. Microsc Res Tech. 2001;52(2):204–23.PubMedCrossRefGoogle Scholar
  241. 241.
    Feldman M, Ruan W, Cunningham BC, Wells JA, Kleinberg DL. Evidence that the growth hormone receptor mediates differentiation and development of the mammary gland. Endocrinology. 1993;133(4):1602–8.PubMedGoogle Scholar
  242. 242.
    Marshman E, Streuli CH. Insulin-like growth factors and insulin-like growth factor binding proteins in mammary gland function. Breast Cancer Res. 2002;4(6):231–9.PubMedPubMedCentralCrossRefGoogle Scholar
  243. 243.
    Howlin J, McBryan J, Martin F. Pubertal mammary gland development: insights from mouse models. J Mammary Gland Biol Neoplasia. 2006;11(3–4):283–97.PubMedCrossRefGoogle Scholar
  244. 244.
    Going JJ, Anderson TJ, Battersby S, MacIntyre CC. Proliferative and secretory activity in human breast during natural and artificial menstrual cycles. Am J Pathol. 1988;130(1):193–204.PubMedPubMedCentralGoogle Scholar
  245. 245.
    Ramakrishnan R, Khan SA, Badve S. Morphological changes in breast tissue with menstrual cycle. Mod Pathol. 2002;15(12):1348–56.PubMedCrossRefGoogle Scholar
  246. 246.
    Navarrete MA, Maier CM, Falzoni R, Quadros LG, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  247. 247.
    Andres AC, Strange R. Apoptosis in the estrous and menstrual cycles. J Mammary Gland Biol Neoplasia. 1999;4(2):221–8.PubMedCrossRefGoogle Scholar
  248. 248.
    Fanager H, Ree HJ. Cyclic changes of human mammary gland epithelium inrelation to the menstrual cycle–an ultrastructural study. Cancer. 1974;34:574–85.CrossRefGoogle Scholar
  249. 249.
    Ferguson JE, Schor AM, Howell A, Ferguson MW. Changes in the extracellular matrix of the normal human breast during the menstrual cycle. Cell Tissue Res. 1992;268(1):167–77.PubMedCrossRefGoogle Scholar
  250. 250.
    McCarty KS Jr, Sasso R, Budwit D, Georgiade GS, Seigler HF. Immunoglobulin localization in the normal human mammary gland: variation with the menstrual cycle. Am J Pathol. 1982;107(3):322–6.PubMedPubMedCentralGoogle Scholar
  251. 251.
    Kass R, Mancino AT, Rosenbloom A L, Klimberg VS, Bland KI. Breast physiology: normal and abnormal development and function. In: Bland KI, Copeland III EM, editors. The breast: comprehensive management of benign and malignant disorders. 3rd ed. St. Louis, Missouri: Saunders; 2004.Google Scholar
  252. 252.
    Silva JS, Georgiade GS, Dilley WG, McCarty KS Sr, Wells SA Jr, McCarty KS Jr. Menstrual cycle-dependent variations of breast cyst fluid proteins and sex steroid receptors in the normal human breast. Cancer. 1983;51(7):1297–302.PubMedCrossRefGoogle Scholar
  253. 253.
    Fabris G, Marchetti E, Marzola A, Bagni A, Guerzoli P, Nenci I. Pathophysiology of estrogen receptors in mammary tissue by monoclonal antibodies. J Steroid Biochem. 1987;27:171–6.PubMedCrossRefGoogle Scholar
  254. 254.
    Dabrosin C. Increased extracellular local levels of estradiol in normal breast in vivo during the luteal phase of the menstrual cycle. J Endocrinol. 2005;187(1):103–8.PubMedCrossRefGoogle Scholar
  255. 255.
    Gompel A, Martin A, Simon P, Schoevaert D, Plu-Bureau G, Hugol D, et al. Epidermal growth factor receptor and c-erbB-2 expression in normal breast tissue during the menstrual cycle. Breast Cancer Res Treat. 1996;38(2):227–35.PubMedCrossRefGoogle Scholar
  256. 256.
    Nevalainen MT, Xie J, Bubendorf L, Wagner KU, Rui H. Basal activation of transcription factor signal transducer and activator of transcription (Stat5) in nonpregnant mouse and human breast epithelium. Mol Endocrinol. 2002;16(5):1108–24.Google Scholar
  257. 257.
    Ham AW. Histology. 6th ed. Philadelphia: J.B. Lippincott Company; 1969.Google Scholar
  258. 258.
    Russell TD, Palmer CA, Orlicky DJ, Fischer A, Rudolph MC, Neville MC, et al. Cytoplasmic lipid droplet accumulation in developing mammary epithelial cells: roles of adipophilin and lipid metabolism. J Lipid Res. 2007;48(7):1463–75.PubMedCrossRefGoogle Scholar
  259. 259.
    Piliero SJ, Jacobs MS, Wischnitzer S. Atlas of histology. Philadelphia: J.B. Lippincott Company; 1965.Google Scholar
  260. 260.
    Medina D. Mammary developmental fate and breast cancer risk. Endocr Relat Cancer. 2005;12(3):483–95.PubMedCrossRefGoogle Scholar
  261. 261.
    Balogh GA, Heulings R, Mailo DA, Russo PA, Sheriff F, Russo IH, et al. Genomic signature induced by pregnancy in the human breast. Int J Oncol. 2006;28(2):399–410.PubMedGoogle Scholar
  262. 262.
    Popnikolov N, Yang J, Liu A, Guzman R, Nandi S. Reconstituted normal human breast in nude mice: effect of host pregnancy environment and human chorionic gonadotropin on proliferation. J Endocrinol. 2001;168(3):487–96.PubMedCrossRefGoogle Scholar
  263. 263.
    Numan M. Maternal behavior. In: Knobil E, Neill JD, editors. The physiology of reproduction. New York: Raven Press; 1994. p. 221–302.Google Scholar
  264. 264.
    Eliassen AH, Tworoger SS, Hankinson SE. Reproductive factors and family history of breast cancer in relation to plasma prolactin levels in premenopausal and postmenopausal women. Int J Cancer. 2007;120(7):1536–41.PubMedCrossRefGoogle Scholar
  265. 265.
    Blakely CM, Stoddard AJ, Belka GK, Dugan KD, Notarfrancesco KL, Moody SE, et al. Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy. Cancer Res. 2006;66(12):6421–31.PubMedCrossRefGoogle Scholar
  266. 266.
    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.PubMedGoogle Scholar
  267. 267.
    Russo J, Moral R, Balogh GA, Mailo D, Russo IH. The protective role of pregnancy in breast cancer. Breast Cancer Res. 2005;7(3):131–42.PubMedPubMedCentralCrossRefGoogle Scholar
  268. 268.
    Jackson D, Bresnick J, Dickson C. A role for fibroblast growth factor signaling in the lobuloalveolar development of the mammary gland. J Mammary Gland Biol Neoplasia. 1997;2(4):385–92.PubMedCrossRefGoogle Scholar
  269. 269.
    Laud K, Hornez L, Gourdou I, Belair L, Arnold A, Peyrat JP, et al. Expression of BRCA1 gene in ewe mammary epithelial cells during pregnancy: regulation by growth hormone and steroid hormones. Eur J Endocrinol/Eur Fed Endocr Soc. 2001;145(6):763–70.CrossRefGoogle Scholar
  270. 270.
    Furuta S, Jiang X, Gu B, Cheng E, Chen PL, Lee WH. Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells. Proc Natl Acad Sci USA. 2005;102(26):9176–81.PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Burkitt HG, Young B, Heathe JW. Wheater’s functional histology, a text and coulour atlas. 3rd ed. Edinburgh: Churchill Livingstone; 1993.Google Scholar
  272. 272.
    Espinosa LA, Daniel BL, Vidarsson L, Zakhour M, Ikeda DM, Herfkens RJ. The lactating breast: contrast-enhanced MR imaging of normal tissue and cancer. Radiology. 2005;237(2):429–36.PubMedCrossRefGoogle Scholar
  273. 273.
    Forsyth I. Mammary gland, overview. In: Knobil E, Neill JD, editors. Encyclopedia of reproduction. 1999: Cambridge: Academic Press; 1999. p. 81–8.Google Scholar
  274. 274.
    Neville MC. Milk secretion: an overview. Denver, CO1998 [updated 199807/31/2007]; Available from:
  275. 275.
    Itoh M, Bissell MJ. The organization of tight junctions in epithelia: implications for mammary gland biology and breast tumorigenesis. J Mammary Gland Biol Neoplasia. 2003;8(4):449–62.PubMedPubMedCentralCrossRefGoogle Scholar
  276. 276.
    Young B, Wheater PR. Wheater’s functional histology: a text and colour atlas. 5th ed. Oxford: Churchill Livingstone Elsevier; 2006. x, 437p.Google Scholar
  277. 277.
    Kolb AF. Engineering immunity in the mammary gland. J Mammary Gland Biol Neoplasia. 2002;7(2):123–34.PubMedCrossRefGoogle Scholar
  278. 278.
    Uauy R, De Andraca I. Human milk and breast feeding for optimal mental development. J Nutr. 1995;125(8 Suppl):2278S–80S.PubMedGoogle Scholar
  279. 279.
    Lawson M. Contemporary aspects of infant feeding. Paediatr Nurs. 2007;19(2):39–46.PubMedCrossRefGoogle Scholar
  280. 280.
    Owen CG, Whincup PH, Gilg JA, Cook DG. Effect of breast feeding in infancy on blood pressure in later life: systematic review and meta-analysis. BMJ. 2003;327(7425):1189–95.PubMedPubMedCentralCrossRefGoogle Scholar
  281. 281.
    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):1446–57.PubMedCrossRefGoogle Scholar
  282. 282.
    Frank JW, Newman J. Breast-feeding in a polluted world: uncertain risks, clear benefits. CMAJ. 1993;149(1):33–7.PubMedPubMedCentralGoogle Scholar
  283. 283.
    Rudolph MC, McManaman JL, Phang T, Russell T, Kominsky DJ, Serkova NJ, et al. Metabolic regulation in the lactating mammary gland: a lipid synthesizing machine. Physiol Genomics. 2007;28(3):323–36.PubMedCrossRefGoogle Scholar
  284. 284.
    Villalpando S, del Prado M. Interrelation among dietary energy and fat intakes, maternal body fatness, and milk total lipid in humans. J Mammary Gland Biol Neoplasia. 1999;4(3):285–95.PubMedCrossRefGoogle Scholar
  285. 285.
    Neville MC. Calcium secretion into milk. J Mammary Gland Biol Neoplasia. 2005;10(2):119–28.PubMedCrossRefGoogle Scholar
  286. 286.
    Keenan TS, Franke WW, Mather IH, Morre DJ. Endomembrane composition and function in milk formation. In: Larson BL, editor. Lactation. New York: Academic Press, Inc.; 1978. p. 105.Google Scholar
  287. 287.
    Linzell JL, Peaker M. Mechanism of milk secretion. Physiol Rev. 1971;51(3):564–97.PubMedGoogle Scholar
  288. 288.
    Neville MC. The physiological basis of milk secretion. Ann NY Acad Sci. 1990;586:1–11.PubMedCrossRefGoogle Scholar
  289. 289.
    Fleishaker JC, McNamara PJ. In vivo evaluation in the lactating rabbit of a model for xenobiotic distribution into breast milk. J Pharmacol Exp Ther. 1988;244(3):919–24.PubMedGoogle Scholar
  290. 290.
    Hunziker W, Kraehenbuhl JP. Epithelial transcytosis of immunoglobulins. J Mammary Gland Biol Neoplasia. 1998;3(3):287–302.PubMedCrossRefGoogle Scholar
  291. 291.
    Csontos K, Rust M, Hollt V, Mahr W, Kromer W, Teschemacher HJ. Elevated plasma beta-endorphin levels in pregnant women and their neonates. Life Sci. 1979;25(10):835–44.PubMedCrossRefGoogle Scholar
  292. 292.
    Clevenger CV, Plank TL. Prolactin as an autocrine/paracrine factor in breast tissue. J Mammary Gland Biol Neoplasia. 1997;2(1):59–68.PubMedCrossRefGoogle Scholar
  293. 293.
    Mol JA, Lantinga-van Leeuwen I, van Garderen E, Rijnberk A. Progestin-induced mammary growth hormone (GH) production. Adv Exp Med Biol. 2000;480:71–6.Google Scholar
  294. 294.
    McNeilly AS, Robinson IC, Houston MJ, Howie PW. Release of oxytocin and prolactin in response to suckling. Br Med J. 1983;286(6361):257–9.Google Scholar
  295. 295.
    Martin RH, Oakey RE. The role of antenatal oestrogen in post-partum human lactogenesis: evidence from oestrogen-deficient pregnancies. Clin Endocrinol. 1982;17(4):403–8.CrossRefGoogle Scholar
  296. 296.
    Daly SE, Kent JC, Owens RA, Hartmann PE. Frequency and degree of milk removal and the short-term control of human milk synthesis. Exp Physiol. 1996;81(5):861–75.PubMedCrossRefGoogle Scholar
  297. 297.
    Hadsell D, George J, Torres D. The declining phase of lactation: peripheral or central, programmed or pathological? J Mammary Gland Biol Neoplasia. 2007;12(1):59–70.Google Scholar
  298. 298.
    Itahana Y, Piens M, Sumida T, Fong S, Muschler J, Desprez PY. Regulation of clusterin expression in mammary epithelial cells. Exp Cell Res. 2007;313(5):943–51.PubMedCrossRefGoogle Scholar
  299. 299.
    Mennella JA, Pepino MY, Teff KL. Acute alcohol consumption disrupts the hormonal milieu of lactating women. J Clin Endocrinol Metab. 2005;90(4):1979–85.PubMedCrossRefGoogle Scholar
  300. 300.
    Butte NF, Hopkinson JM. Body composition changes during lactation are highly variable among women. J Nutr. 1998;128(2 Suppl):381S–5S.PubMedGoogle Scholar
  301. 301.
    Ganong W. Review of medical physiology. 22nd ed: New York: Lange; 2005.Google Scholar
  302. 302.
    Dewey KG. Effects of maternal caloric restriction and exercise during lactation. J Nutr. 1998;128(2 Suppl):386S–9S.PubMedGoogle Scholar
  303. 303.
    Wysolmerski J. Calcium handling by the lactating breast and its relationship to calcium-related complications of breast cancer. J Mammary Gland Biol Neoplasia. 2005;10(2):101–3.PubMedCrossRefGoogle Scholar
  304. 304.
    Kovacs CS. Calcium and bone metabolism during pregnancy and lactation. J Mammary Gland Biol Neoplasia. 2005;10(2):105–18.PubMedCrossRefGoogle Scholar
  305. 305.
    Wilde CJ, Knight CH, Flint DJ. Control of milk secretion and apoptosis during mammary involution. J Mammary Gland Biol Neoplasia. 1999;4(2):129–36.PubMedCrossRefGoogle Scholar
  306. 306.
    Talhouk RS, Bissell MJ, Werb Z. Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution. J Cell Biol. 1992;118(5):1271–82.PubMedCrossRefGoogle Scholar
  307. 307.
    Marti A, Lazar H, Ritter P, Jaggi R. Transcription factor activities and gene expression during mouse mammary gland involution. J Mammary Gland Biol Neoplasia. 1999;4(2):145–52.PubMedCrossRefGoogle Scholar
  308. 308.
    Stein T, Salomonis N, Gusterson BA. Mammary gland involution as a multi-step process. J Mammary Gland Biol Neoplasia. 2007;12(1):25–35.PubMedCrossRefGoogle Scholar
  309. 309.
    Watson CJ, Kreuzaler PA. Remodeling mechanisms of the mammary gland during involution. Int J Dev Biol. 2011;55(7–9):757–62 Epub 2011/12/14.PubMedCrossRefGoogle Scholar
  310. 310.
    Jaggi R. Morphological changes during programmed cell death (PCD) in the involuting mouse mammary gland. 1996; Available from:
  311. 311.
    Baxter FO, Neoh K, Tevendale MC. The beginning of the end: death signaling in early involution. J Mammary Gland Biol Neoplasia. 2007;12(1):3–13.PubMedCrossRefGoogle Scholar
  312. 312.
    Thorburn A. Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis. 2007;online first.Google Scholar
  313. 313.
    Atabai K, Sheppard D, Werb Z. Roles of the innate immune system in mammary gland remodeling during involution. J Mammary Gland Biol Neoplasia. 2007;12(1):37–45.PubMedPubMedCentralCrossRefGoogle Scholar
  314. 314.
    Fadok VA. Clearance: the last and often forgotten stage of apoptosis. J Mammary Gland Biol Neoplasia. 1999;4(2):203–11.PubMedCrossRefGoogle Scholar
  315. 315.
    Watson CJ. Involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ. Breast Cancer Res. 2006;8(2):203.PubMedPubMedCentralCrossRefGoogle Scholar
  316. 316.
    Streuli CH, Gilmore AP. Adhesion-mediated signaling in the regulation of mammary epithelial cell survival. J Mammary Gland Biol Neoplasia. 1999;4(2):183–91.PubMedCrossRefGoogle Scholar
  317. 317.
    Martinez-Hernandez A, Fink LM, Pierce GB. Removal of basement membrane in the involuting breast. Lab Invest; a journal of technical methods and pathology. 1976;34(5):455–62.Google Scholar
  318. 318.
    Simpson HW, McArdle CS, George WD, Griffiths K, Turkes A, Pauson AW. Pregnancy postponement and childlessness leads to chronic hypervascularity of the breasts and cancer risk. Br J Cancer. 2002;87(11):1246–52.PubMedPubMedCentralCrossRefGoogle Scholar
  319. 319.
    Flint DJ, Tonner E, Allan GJ. Insulin-like growth factor binding proteins: IGF-dependent and -independent effects in the mammary gland. J Mammary Gland Biol Neoplasia. 2000;5(1):65–73.PubMedCrossRefGoogle Scholar
  320. 320.
    Lochrie JD, Phillips K, Tonner E, Flint DJ, Allan GJ, Price NC, et al. Insulin-like growth factor binding protein (IGFBP)-5 is upregulated during both differentiation and apoptosis in primary cultures of mouse mammary epithelial cells. J Cell Physiol. 2006;207(2):471–9.PubMedCrossRefGoogle Scholar
  321. 321.
    Mikkola ML, Millar SE. The mammary bud as a skin appendage: unique and shared aspects of development. J Mammary Gland Biol Neoplasia. 2006;11(3–4):187–203.PubMedCrossRefGoogle Scholar
  322. 322.
    Dillon C, Spencer-Dene B, Dickson C. A crucial role for fibroblast growth factor signaling in embryonic mammary gland development. J Mammary Gland Biol Neoplasia. 2004;9(2):207–15.PubMedCrossRefGoogle Scholar
  323. 323.
    Watson CJ, Burdon TG. Prolactin signal transduction mechanisms in the mammary gland: the role of the Jak/Stat pathway. Rev Reprod. 1996;1(1):1–5.PubMedCrossRefGoogle Scholar
  324. 324.
    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(22):1704–11.PubMedCrossRefGoogle Scholar
  325. 325.
    Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 2004;6(6):R605–15.PubMedPubMedCentralCrossRefGoogle Scholar
  326. 326.
    Dontu G, Wicha MS. Survival of mammary stem cells in suspension culture: implications for stem cell biology and neoplasia. J Mammary Gland Biol Neoplasia. 2005;10(1):75–86.PubMedCrossRefGoogle Scholar
  327. 327.
    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):109–18.PubMedCrossRefGoogle Scholar
  328. 328.
    Lewis MT, Veltmaat JM. Next stop, the twilight zone: hedgehog network regulation of mammary gland development. J Mammary Gland Biol Neoplasia. 2004;9(2):165–81.PubMedCrossRefGoogle Scholar
  329. 329.
    Hatsell S, Frost AR. Hedgehog signaling in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2007;12(2–3):163–73.PubMedCrossRefGoogle Scholar
  330. 330.
    Groner B. Transcription factor regulation in mammary epithelial cells. Domest Anim Endocrinol. 2002;23(1–2):25–32.PubMedCrossRefGoogle Scholar
  331. 331.
    Zhou J, Chehab R, Tkalcevic J, Naylor MJ, Harris J, Wilson TJ, et al. Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation. EMBO J. 2005;24(3):635–44.PubMedPubMedCentralCrossRefGoogle Scholar
  332. 332.
    Puppin C, Puglisi F, Pellizzari L, Manfioletti G, Pestrin M, Pandolfi M, et al. HEX expression and localization in normal mammary gland and breast carcinoma. BMC Cancer. 2006;6:192.PubMedPubMedCentralCrossRefGoogle Scholar
  333. 333.
    van Genderen C, Okamura RM, Farinas I, Quo RG, Parslow TG, Bruhn L, et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev. 1994;8(22):2691–703 Epub 1994/11/15.PubMedCrossRefGoogle Scholar
  334. 334.
    Davenport TG, Jerome-Majewska LA, Papaioannou VE. Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development. 2003;130(10):2263–73. Epub 2003/04/02.Google Scholar
  335. 335.
    Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet. 2000;24(4):391–5 Epub 2000/03/31.PubMedCrossRefGoogle Scholar
  336. 336.
    Dunbar ME, Wysolmerski JJ. Parathyroid hormone-related protein: a developmental regulatory molecule necessary for mammary gland development. J Mammary Gland Biol Neoplasia. 1999;4(1):21–34 Epub 1999/04/29.PubMedCrossRefGoogle Scholar
  337. 337.
    Kim H, Laing M, Muller W. c-Src-null mice exhibit defects in normal mammary gland development and ERalpha signaling. Oncogene. 2005;24(36):5629–36 Epub 2005/07/12.PubMedCrossRefGoogle Scholar
  338. 338.
    Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995;9(18):2266–78 Epub 1995/09/15.PubMedCrossRefGoogle Scholar
  339. 339.
    Horseman ND, Zhao W, Montecino-Rodriguez E, Tanaka M, Nakashima K, Engle SJ, et al. Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J. 1997;16(23):6926–35 Epub 1998/01/31.PubMedPubMedCentralCrossRefGoogle Scholar
  340. 340.
    Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev. 1997;11(2):179–86 Epub 1997/01/15.PubMedCrossRefGoogle Scholar
  341. 341.
    Wagner KU, Krempler A, Triplett AA, Qi Y, George NM, Zhu J, et al. Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. Mol Cell Biol. 2004;24(12):5510–20 Epub 2004/06/01.PubMedPubMedCentralCrossRefGoogle Scholar
  342. 342.
    Stinnakre MG, Vilotte JL, Soulier S, Mercier JC. Creation and phenotypic analysis of alpha-lactalbumin-deficient mice. Proc Natl Acad Sci USA. 1994;91(14):6544–8 Epub 1994/07/05.PubMedPubMedCentralCrossRefGoogle Scholar
  343. 343.
    Triplett AA, Sakamoto K, Matulka LA, Shen L, Smith GH, Wagner KU. Expression of the whey acidic protein (Wap) is necessary for adequate nourishment of the offspring but not functional differentiation of mammary epithelial cells. Genesis. 2005;43(1):1–11 Epub 2005/08/18.PubMedCrossRefGoogle Scholar
  344. 344.
    Wagner KU, Young WS 3rd, Liu X, Ginns EI, Li M, Furth PA, et al. Oxytocin and milk removal are required for post-partum mammary-gland development. Genes Funct. 1997;1(4):233–44 Epub 1998/07/25.PubMedCrossRefGoogle Scholar
  345. 345.
    Pollard JW, Hennighausen L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc Natl Acad Sci USA. 1994;91(20):9312–6 Epub 1994/09/27.PubMedPubMedCentralCrossRefGoogle Scholar
  346. 346.
    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 Epub 1995/10/01.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Anatomy, Physiology and GeneticsUniformed Services UniversityBethesdaUSA
  2. 2.Department of PathologyUniformed Services UniversityBethesdaUSA

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