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Mammary Glands, Stem Cells and Breast Cancer

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Breast Cancer in the Post-Genomic Era

Part of the book series: Current Clinical Oncology ((CCO))

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Summary

The mammary gland is unique in that most of its development occurs after birth with dramatic changes in proliferation and differentiation taking place during puberty and pregnancy. Different subsets of mammary-specific stem/progenitor cells have been shown to drive the individual stages of mammary gland development, and their regulation requires coordination between localized signals and systemic hormones. That sophisticated integration and control is achieved through the function of the stem cell niche. The goal of this chapter is to review why somatic stem cells are thought to exist in the mouse mammary gland, how they are being isolated and assayed, how their fate is influenced by the surrounding microenvironment, and how aberrant regulation of this process might contribute to breast cancer. If the components of the niche could be defined, each might then be targeted as a method to modify the fate of stem or progenitor cells during normal organ regeneration or repaired after tumorigenesis has been initiated.

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References

  1. 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;100:3983–8.

    Article  CAS  PubMed  Google Scholar 

  2. Callahan R, Smith GH. MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways. Oncogene 2000;19:992–1001.

    Article  CAS  PubMed  Google Scholar 

  3. Smith GH. Stem cells and mammary cancer in mice. Stem Cell Rev 2005;1:215–23.

    Article  CAS  PubMed  Google Scholar 

  4. Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821–8.

    CAS  PubMed  Google Scholar 

  5. Thordarson G, Slusher N, Leong H, et al. Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-alpha activation via the mitogen-activated protein kinase pathway. Breast Cancer Res 2004;6:R423–R436.

    Article  CAS  PubMed  Google Scholar 

  6. Sivaraman L, Medina D. Hormone-induced protection against breast cancer. J Mammary Gland Biol Neoplasia 2002;7:77–92.

    Article  PubMed  Google Scholar 

  7. D’Cruz CM, Moody SE, Master SR, et al. Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol 2002;16:2034–51.

    Article  PubMed  Google Scholar 

  8. Ginger MR, Gonzalez-Rimbau MF, Gay JP, Rosen JM. Persistent changes in gene expression induced by estrogen and progesterone in the rat mammary gland. Mol Endocrinol 2001;15:1993–2009.

    Article  CAS  PubMed  Google Scholar 

  9. Boulanger CA, Wagner KU, Smith GH. Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene 2005;24:552–60.

    Article  CAS  PubMed  Google Scholar 

  10. Ludwig T, Fisher P, Murty V, Efstratiadis A. Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice. Oncogene 2001;20:3937–48.

    Article  CAS  PubMed  Google Scholar 

  11. Smith GH. Experimental mammary epithelial morphogenesis in an in vivo model: evidence for distinct cellular progenitors of the ductal and lobular phenotype. Breast Cancer Res Treat 1996;39:21–31.

    Article  CAS  PubMed  Google Scholar 

  12. Kordon EC, Smith GH. An entire functional mammary gland may comprise the progeny from a single cell. Development 1998;125:1921–30.

    CAS  PubMed  Google Scholar 

  13. Kamiya K, Gould MN, Clifton KH. Quantitative studies of ductal versus alveolar differentiation from rat mammary clonogens. Proc Soc Exp Biol Med 1998;219:217–25.

    CAS  PubMed  Google Scholar 

  14. Boulanger CA, Smith GH. Reducing mammary cancer risk through premature stem cell senescence. Oncogene 2001;20:2264–72.

    Article  CAS  PubMed  Google Scholar 

  15. Henry MD, Triplett AA, Oh KB, Smith GH, Wagner KU. Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-neu transgenic mice. Oncogene 2004;23:6980–5.

    Article  CAS  PubMed  Google Scholar 

  16. Krempler A, Henry MD, Triplett AA, Wagner KU. Targeted deletion of the Tsg101 gene results in cell cycle arrest at G1/S and p53-independent cell death. J Biol Chem 2002;277:43216–23.

    Article  CAS  PubMed  Google Scholar 

  17. Cairns J. Mutation selection and the natural history of cancer. Nature 1975;255:197–200.

    Article  CAS  PubMed  Google Scholar 

  18. Potten CS, Owen G, Booth D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 2002;115:2381–8.

    CAS  PubMed  Google Scholar 

  19. Smith GH. Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development 2005;132:681–7.

    Article  CAS  PubMed  Google Scholar 

  20. DeOme KB, Faulkin LJ Jr, Bern HA, Blair PB. Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res 1959;19:515–20.

    CAS  PubMed  Google Scholar 

  21. Daniel CW, Deome KB. Growth of mouse mammary glands in vivo after monolayer culture. Science 1965;149:634–6.

    Article  CAS  PubMed  Google Scholar 

  22. Daniel CW, Young LJ. Influence of cell division on an aging process. Life span of mouse mammary epithelium during serial propagation in vivo. Exp Cell Res 1971;65:27–32.

    Article  CAS  PubMed  Google Scholar 

  23. Proia DA, Kuperwasser C. Reconstruction of human mammary tissues in a mouse model. Nat Protoc 2006;1:206–14.

    Article  CAS  PubMed  Google Scholar 

  24. Smith GH, Boulanger CA. Mammary stem cell repertoire: new insights in aging epithelial populations. Mech Ageing Dev 2002;123:1505–19.

    Article  CAS  PubMed  Google Scholar 

  25. Stingl J, Caldas C. Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nat Rev Cancer 2007;7:791–9.

    Article  CAS  PubMed  Google Scholar 

  26. 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:R605–R615.

    Article  CAS  PubMed  Google Scholar 

  27. Booth BW, Boulanger CA, Smith GH. Alveolar progenitor cells develop in mouse mammary glands independent of pregnancy and lactation. J Cell Physiol 2007;212:729–36.

    Article  CAS  PubMed  Google Scholar 

  28. Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006;66:6063–71.

    Article  CAS  PubMed  Google Scholar 

  29. Molyneux G, Regan J, Smalley MJ. Mammary stem cells and breast cancer. Cell Mol Life Sci 2007;64:3248–3260.

    Article  CAS  PubMed  Google Scholar 

  30. Stingl J, Eirew P, Ricketson I, et al. Purification and unique properties of mammary epithelial stem cells. Nature 2006;439:993–7.

    CAS  PubMed  Google Scholar 

  31. Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006;439:84–8.

    Article  CAS  PubMed  Google Scholar 

  32. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747–52.

    Article  CAS  PubMed  Google Scholar 

  33. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001;98:10869–74.

    Article  CAS  PubMed  Google Scholar 

  34. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 2003;100:8418–23.

    Article  CAS  PubMed  Google Scholar 

  35. Foulkes WD, Stefansson IM, Chappuis PO, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 2003;95:1482–5.

    CAS  PubMed  Google Scholar 

  36. Fillmore C, Kuperwasser C. Human breast cancer stem cell markers CD44 and CD24: enriching for cells with functional properties in mice or in man? Breast Cancer Res 2007;9:303.

    Article  PubMed  Google Scholar 

  37. Mahendran R, McIlhinney R, O’Hare M, Monaghan P, Gusterson B. Expression of the common acute lymphoblastic leukaemia antigen (CALLA) in the human breast. Mol Cell Probes 1989;3:39–44.

    Article  CAS  PubMed  Google Scholar 

  38. Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 2007;11:259–73.

    Article  CAS  PubMed  Google Scholar 

  39. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756–60.

    Article  CAS  PubMed  Google Scholar 

  40. Piccirillo SG, Reynolds BA, Zanetti N, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006;444:761–5.

    Article  CAS  PubMed  Google Scholar 

  41. Medina D. Mammary developmental fate and breast cancer risk. Endocr Relat Cancer 2005;12:483–95.

    Article  CAS  PubMed  Google Scholar 

  42. Wagner KU, Boulanger CA, Henry MD, Sgagias M, Hennighausen L, Smith GH. An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development 2002;129:1377–86.

    CAS  PubMed  Google Scholar 

  43. 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;303:29–44.

    Article  CAS  PubMed  Google Scholar 

  44. Pal S, Pegram M. HER2 targeted therapy in breast cancer…beyond Herceptin. Rev Endocr Metab Disord 2007;8:269–77.

    Article  CAS  PubMed  Google Scholar 

  45. Dhesy-Thind B, Pritchard K, Messersmith H, O’Malley F, Elavathil L, Trudeau M. HER2/neu in systemic therapy for women with breast cancer: a systematic review. Breast Cancer Res Treat 2007;109:209–29.

    Article  PubMed  Google Scholar 

  46. Lin H. The stem-cell niche theory: lessons from flies. Nat Rev Genet 2002;3:931–40.

    Article  CAS  PubMed  Google Scholar 

  47. Rizvi AZ, Wong MH. Epithelial stem cells and their niche: there’s no place like home. Stem Cells 2005;23:150–65.

    Article  PubMed  Google Scholar 

  48. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 2006;6:93–106.

    Article  CAS  PubMed  Google Scholar 

  49. Chepko G, Dickson RB. Ultrastructure of the putative stem cell niche in rat mammary epithelium. Tissue Cell 2003;35:83–93.

    Article  CAS  PubMed  Google Scholar 

  50. Chepko G, Slack R, Carbott D, Khan S, Steadman L, Dickson RB. Differential alteration of stem and other cell populations in ducts and lobules of TGFalpha and c-Myc transgenic mouse mammary epithelium. Tissue Cell 2005;37:393–412.

    Article  CAS  PubMed  Google Scholar 

  51. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 1978;4:7–25.

    CAS  PubMed  Google Scholar 

  52. Xie T, Spradling AC. A niche maintaining germ line stem cells in the Drosophila ovary. Science 2000;290:328–30.

    Article  CAS  PubMed  Google Scholar 

  53. Kiger AA, White-Cooper H, Fuller MT. Somatic support cells restrict germline stem cell self-renewal and promote differentiation. Nature 2000;407:750–4.

    Article  CAS  PubMed  Google Scholar 

  54. Crittenden SL, Bernstein DS, Bachorik JL, A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans. Nature 2002;417:660–3.

    Article  CAS  PubMed  Google Scholar 

  55. Ohlstein B, Spradling A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 2006;439:470–4.

    Article  CAS  PubMed  Google Scholar 

  56. Micchelli CA, Perrimon N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 2006;439:475–9.

    Article  CAS  PubMed  Google Scholar 

  57. Stumpf WE, Narbaitz R, Sar M. Estrogen receptors in the fetal mouse. J Steroid Biochem 1980;12:55–64.

    Article  CAS  PubMed  Google Scholar 

  58. Brisken C, Heineman A, Chavarria T, Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev 2000;14:650–4.

    CAS  PubMed  Google Scholar 

  59. Asselin-Labat ML, Shackleton M, Stingl J, Steroid hormone receptor status of mouse mammary stem cells. J Natl Cancer Inst 2006;98:1011–14.

    Article  CAS  PubMed  Google Scholar 

  60. Brisken C, Duss S. Stem cells and the stem cell niche in the breast: an integrated hormonal and developmental perspective. Stem Cell Rev 2007;3:147–56.

    Article  CAS  PubMed  Google Scholar 

  61. Wiesen JF, Young P, Werb Z, Cunha GR. Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. Development 1999;126:335–44.

    CAS  PubMed  Google Scholar 

  62. Ciarloni L, Mallepell S, Brisken C. Amphiregulin is an essential mediator of estrogen receptor alpha function in mammary gland development. Proc Natl Acad Sci USA 2007;104:5455–60.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  64. 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 USA 2003;100:9744–9.

    Article  CAS  PubMed  Google Scholar 

  65. Brisken C, Ayyannan A, Nguyen C, IGF-2 is a mediator of prolactin-induced morphogenesis in the breast. Dev Cell 2002;3:877–87.

    Article  CAS  PubMed  Google Scholar 

  66. Sonnenberg A, Daams H, Van der Valk MA, Hilkens J, Hilgers J. Development of mouse mammary gland: identification of stages in differentiation of luminal and myoepithelial cells using monoclonal antibodies and polyvalent antiserum against keratin. J Histochem Cytochem 1986;34:1037–46.

    CAS  PubMed  Google Scholar 

  67. 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;245:42–56.

    Article  CAS  PubMed  Google Scholar 

  68. Tsai YC, Lu Y, Nichols PW, Zlotnikov G, Jones PA, Smith HS. Contiguous patches of normal human mammary epithelium derived from a single stem cell: implications for breast carcinogenesis. Cancer Res 1996;56:402–4.

    CAS  PubMed  Google Scholar 

  69. Villadsen R, Fridriksdottir AJ, Ronnov-Jessen L, Evidence for a stem cell hierarchy in the adult human breast. J Cell Biol 2007;177:87–101.

    Article  CAS  PubMed  Google Scholar 

  70. Stasiak PC, Purkis PE, Leigh IM, Lane EB. Keratin 19: predicted amino acid sequence and broad tissue distribution suggest it evolved from keratinocyte keratins. J Invest Dermatol 1989;92:707–16.

    Article  CAS  PubMed  Google Scholar 

  71. Dravida S, Pal R, Khanna A, Tipnis SP, Ravindran G, Khan F. The transdifferentiation potential of limbal fibroblast-like cells. Brain Res Dev Brain Res 2005;160:239–51.

    Article  CAS  PubMed  Google Scholar 

  72. Ohyama M, Terunuma A, Tock CL, Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest 2006;116:249–60.

    Article  CAS  PubMed  Google Scholar 

  73. Schmelz M, Moll R, Hesse U, Identification of a stem cell candidate in the normal human prostate gland. Eur J Cell Biol 2005;84:341–54.

    Article  CAS  PubMed  Google Scholar 

  74. Hudson DL, Guy AT, Fry P, O’Hare MJ, Watt FM, Masters JR. Epithelial cell differentiation pathways in the human prostate: identification of intermediate phenotypes by keratin expression. J Histochem Cytochem 2001;49:271–8.

    CAS  PubMed  Google Scholar 

  75. Fuchs E, Tumbar T, Guasch G. Socializing with the neighbors: stem cells and their niche. Cell 2004;116:769–78.

    Article  CAS  PubMed  Google Scholar 

  76. Moraes RC, Zhang X, Harrington N, Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia. Development 2007;134:1231–42.

    Article  CAS  PubMed  Google Scholar 

  77. Nishimura EK, Jordan SA, Oshima H, Dominant role of the niche in melanocyte stem-cell fate determination. Nature 2002;416:854–60.

    Article  CAS  PubMed  Google Scholar 

  78. Collins CA, Olsen I, Zammit PS, Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 2005;122:289–301.

    Article  CAS  PubMed  Google Scholar 

  79. Dreyfus PA, Chretien F, Chazaud B, Adult bone marrow-derived stem cells in muscle connective tissue and satellite cell niches. Am J Pathol 2004;164:773–9.

    Article  PubMed  Google Scholar 

  80. Ferrari G, Cusella-De Angelis G, Coletta M, Muscle regeneration by bone marrow-derived myogenic progenitors. Science 1998;279:1528–30.

    Article  CAS  PubMed  Google Scholar 

  81. Fukada S, Miyagoe-Suzuki Y, Tsukihara H, Muscle regeneration by reconstitution with bone marrow or fetal liver cells from green fluorescent protein-gene transgenic mice. J Cell Sci 2002;115:1285–93.

    CAS  PubMed  Google Scholar 

  82. LaBarge MA, Blau HM. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 2002;111:589–601.

    Article  CAS  PubMed  Google Scholar 

  83. Sherwood RI, Christensen JL, Conboy IM, Isolation of adult mouse myogenic progenitors: functional heterogeneity of cells within and engrafting skeletal muscle. Cell 2004;119:543–54.

    Article  CAS  PubMed  Google Scholar 

  84. Boulanger CA, Mack DL, Booth BW, Smith GH. Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo. Proc Natl Acad Sci USA 2007;104:3871–6.

    Article  CAS  PubMed  Google Scholar 

  85. Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 2004;5:738–43.

    Article  CAS  PubMed  Google Scholar 

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  1. Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA

    David L. Mack, Gilbert H. Smith & Brian W. Booth

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  1. David L. Mack
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  2. Gilbert H. Smith
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    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

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    Mack, D.L., Smith, G.H., Booth, B.W. (2009). Mammary Glands, Stem Cells and Breast Cancer. In: Giordano, A., Normanno, N. (eds) Breast Cancer in the Post-Genomic Era. Current Clinical Oncology. Humana Press. https://doi.org/10.1007/978-1-60327-945-1_2

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    • DOI: https://doi.org/10.1007/978-1-60327-945-1_2

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