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Of Microenvironments and Mammary Stem Cells

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Abstract

In most adult tissues there reside pools of stem and progenitor cells inside specialized microenvironments referred to as niches. The niche protects the stem cells from inappropriate expansion and directs their critical functions. Thus guided, stem cells are able to maintain tissue homeostasis throughout the ebb and flow of metabolic and physical demands encountered over a lifetime. Indeed, a pool of stem cells maintains mammary gland structure throughout development, and responds to the physiological demands associated with pregnancy. This review discusses how stem cells were identified in both human and mouse mammary glands; each requiring different techniques that were determined by differing biological needs and ethical constraints. These studies together create a robust portrait of mammary gland biology and identify the location of the stem cell niche, elucidate a developmental hierarchy, and suggest how the niche might be manipulated for therapeutic benefit.

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References

  1. Deome, K. B., Faulkin, L. J. Jr., Bern, H. A., & Blair, P. B. (1959). Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Research, 19, 515–520.

    PubMed  CAS  Google Scholar 

  2. Kordon, E. C., & Smith, G. H. (1998). An entire functional mammary gland may comprise the progeny from a single cell. Development, 125, 1921–1930.

    PubMed  CAS  Google Scholar 

  3. Tsai, Y. C., Lu, Y., Nichols, P. W., Zlotnikov, G., Jones, P. A., & Smith, H. S. (1996). Contiguous patches of normal human mammary epithelium derived from a single stem cell: Implications for breast carcinogenesis. Cancer Research, 56, 402–404.

    PubMed  CAS  Google Scholar 

  4. Clarke, R. B., Spence, K., Anderson, E., Howell, A., Okano, H., & Potten, C. S. (2005a). A putative human breast stem cell population is enriched for steroid receptor-positive cells. Developmental Biology, 277, 443–456.

    Article  CAS  Google Scholar 

  5. Kang, K. S., Morita, I., Cruz, A., Jeon, Y. J., Trosko, J. E., & Chang, C. C. (1997). Expression of estrogen receptors in a normal human breast epithelial cell type with luminal and stem cell characteristics and its neoplastically transformed cell lines. Carcinogenesis, 18, 251–257.

    Article  PubMed  CAS  Google Scholar 

  6. Kao, C.Y., Nomata, K., Oakley, C. S., Welsch, C. W., & Chang, C. C. (1995). Two types of normal human breast epithelial cells derived from reduction mammoplasty: Phenotypic characterization and response to SV40 transfection. Carcinogenesis, 16, 531–538.

    Article  PubMed  CAS  Google Scholar 

  7. Pechoux, C., Gudjonsson, T., Ronnov-Jessen, L., Bissell, M. J., & Petersen, O. W. (1999). Human mammary luminal epithelial cells contain progenitors to myoepithelial cells. Developmental Biology, 206, 88–99.

    Article  PubMed  CAS  Google Scholar 

  8. Stingl, J., Eirew, P., Ricketson, I., Shackleton, M., Vaillant, F., Choi, D. et al. (2006a). Purification and unique properties of mammary epithelial stem cells. Nature, 439, 993–997.

    CAS  Google Scholar 

  9. Shackleton, M., Vaillant, F., Simpson, K. J., Stingl, J., Smyth, G. K., Asselin-Labat, M. L.,et al. (2006). Generation of a functional mammary gland from a single stem cell. Nature, 439, 84–88.

    Article  PubMed  CAS  Google Scholar 

  10. Howard, B. A., & Gusterson, B. A. (2000). Human breast development. Journal of Mammary Gland Biology and Neoplasia, 5, 119–137.

    Article  PubMed  CAS  Google Scholar 

  11. Sonnenberg, A., Daams, H.,van der Valk, M. A.,Hilkens, J., & Hilgers, J. (1986). Development of mouse mammary gland: Identification of stages in differentiation of luminal and myoepithelial cells using monoclonal antibodies and polyvalent antiserum against keratin. Journal of Histochemistry and Cytochemistry, 34, 1037–1046.

    PubMed  CAS  Google Scholar 

  12. Welm, B. E., Tepera, S. B., Venezia, T., Graubert, T. A., Rosen, J. M., & Goodell, M. A. (2002). Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Developmental Biology, 245, 42–56.

    Article  PubMed  CAS  Google Scholar 

  13. Boulanger, C. A., Wagner, K. U., & Smith, G. H. (2005). Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene, 24, 552–560.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. Clarke, R. B., Spence, K., Anderson, E., Howell, A., Okano, H., & Potten, C. S. (2005b). A putative human breast stem cell population is enriched for steroid receptor-positive cells. Developmental Biology, 277, 443–456.

    Article  CAS  Google Scholar 

  16. Dontu, G., Abdallah, W. M., Foley, J. M., Jackson, K. W., Clarke, M. F., Kawamura, M. J.et al. (2003a). In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes & Development, 17, 1253–1270.

    Article  CAS  Google Scholar 

  17. Gudjonsson, T., Villadsen, R., Nielsen, H. L., Ronnov-Jessen, L., Bissell, M. J., & Petersen, O. W. (2002a). Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties. Genes and Development, 16, 693–706.

    Article  CAS  Google Scholar 

  18. Stingl, J., Eirew, P., Ricketson, I., Shackleton, M., Vaillant, F., Choi, D., et al. (2006b). Purification and unique properties of mammary epithelial stem cells. Nature, 439, 993–997.

    CAS  Google Scholar 

  19. Villadsen, R., Fridriksdottir, A. J., Ronnov-Jessen, L., Gudjonsson, T., Rank, F., LaBarge, M. A., et al. (2007). Evidence for a stem cell hierarchy in the adult human breast. Journal of Cell Biology, 177, 87–101.

    Article  PubMed  CAS  Google Scholar 

  20. Dontu, G., Jackson, K. W., McNicholas, E., Kawamura, M. J., Wissam, M. A., Wicha, M. S., (2004). Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Research, 6, R605–R615.

    Article  PubMed  CAS  Google Scholar 

  21. Fuchs, E., Tumbar, T., & Guasch, G. (2004). Socializing with the neighbors: Stem cells and their niche. Cell, 116, 769–778.

    Article  PubMed  CAS  Google Scholar 

  22. Moll, I. (1995). Proliferative potential of different keratinocytes of plucked human hair follicles. Journal of Investigative Dermatology, 105, 14–21.

    Article  PubMed  CAS  Google Scholar 

  23. Tumbar, T., Guasch, G., Greco, V., Blanpain, C., Lowry, W. E., Rendl, M., et al. (2004). Defining the epithelial stem cell niche in skin. Science, 303, 359–363.

    Article  PubMed  CAS  Google Scholar 

  24. Yang, J. S., Lavker, R. M., & Sun, T. T. (1993). Upper human hair follicle contains a subpopulation of keratinocytes with superior in vitro proliferative potential. Journal of Investigative Dermatology, 101, 652–659.

    Article  PubMed  CAS  Google Scholar 

  25. Tsujimura, A., Koikawa, Y., Salm, S., Takao, T., Coetzee, S., Moscatelli, D., et al. (2002). Proximal location of mouse prostate epithelial stem cells: A model of prostatic homeostasis. Journal of Cell Biology, 157, 1257–1265.

    Article  PubMed  CAS  Google Scholar 

  26. O’Hare, M. J., Ormerod, M. G., Monaghan, P., Lane, E. B., & Gusterson, B. A. (1991). Characterization in vitro of luminal and myoepithelial cells isolated from the human mammary gland by cell sorting. Differentiation, 46, 209–221.

    Article  PubMed  CAS  Google Scholar 

  27. Bocker, W., Moll, R., Poremba, C., Holland, R., Van Diest, P. J., Dervan, P., et al. (2002). Common adult stem cells in the human breast give rise to glandular and myoepithelial cell lineages: A new cell biological concept. Laboratory Investigation, 82, 737–746.

    PubMed  Google Scholar 

  28. Dravida, S., Pal, R., Khanna, A., Tipnis, S. P., Ravindran, G., & Khan, F. (2005). The transdifferentiation potential of limbal fibroblast-like cells. Brain Research. Developmental Brain Research, 160, 239–251.

    Article  PubMed  CAS  Google Scholar 

  29. Ohyama, M., Terunuma, A., Tock, C. L., Radonovich, M. F., Pise-Masison, C. A., Hopping, et al. (2006). Characterization and isolation of stem cell-enriched human hair follicle bulge cells. Journal of Clinical Investigation, 116, 249–260.

    Article  PubMed  CAS  Google Scholar 

  30. Schmelz, M., Moll, R., Hesse, U., Prasad, A. R., Gandolfi, J. A., Hasan, S. R., et al. (2005). Identification of a stem cell candidate in the normal human prostate gland. European Journal of Cell Biology, 84, 341–354.

    Article  PubMed  CAS  Google Scholar 

  31. Stasiak, P. C., Purkis, P. E., Leigh, I. M., & Lane, E. B. (1989). Keratin 19: Predicted amino acid sequence and broad tissue distribution suggest it evolved from keratinocyte keratins. Journal of Investigative Dermatology, 92, 707–716.

    Article  PubMed  CAS  Google Scholar 

  32. Hudson, D. L., Guy, A. T., Fry, P., O’Hare, M. J., Watt, F. M., & Masters, J. R. (2001). Epithelial cell differentiation pathways in the human prostate: Identification of intermediate phenotypes by keratin expression. Journal of Histochemistry and Cytochemistry, 49, 271–278.

    PubMed  CAS  Google Scholar 

  33. Stingl, J., Eaves, C. J., Zandieh, I., & Emerman, J. T. (2001). Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue. Breast Cancer Research and Treatment, 67, 93–109.

    Article  PubMed  CAS  Google Scholar 

  34. Gudjonsson, T., Villadsen, R., Nielsen, H. L., Ronnov-Jessen, L., Bissell, M. J., & Petersen, O. W. (2002b). Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties. Genes and Development, 16, 693–706.

    Article  CAS  Google Scholar 

  35. Asselin-Labat, M. L., Sutherland, K. D., Barker, H., Thomas, R., Shackleton, M., Forrest, N. C., et al. (2007). Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nature Cell Biology, 9, 201–209.

    Article  PubMed  CAS  Google Scholar 

  36. Kouros-Mehr, H., Slorach, E. M., Sternlicht, M. D., & Werb, Z. (2006). GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell, 127, 1041–1055.

    Article  PubMed  CAS  Google Scholar 

  37. Buono, K. D., Robinson, G. W., Martin, C., Shi, S., Stanley, P., Tanigaki, K.,et al. (2006). The canonical Notch/RBP-J signaling pathway controls the balance of cell lineages in mammary epithelium during pregnancy. Developmental Biology, 293, 565–580.

    Article  PubMed  CAS  Google Scholar 

  38. Matulka, L. A., Triplett, A. A., & Wagner, K. U. (2007). Parity-induced mammary epithelial cells are multipotent and express cell surface markers associated with stem cells. Developmental Biology, 303, 29–44.

    Article  PubMed  CAS  Google Scholar 

  39. Dimri, G., Band, H., & Band, V. (2005). Mammary epithelial cell transformation: insights from cell culture and mouse models. Breast Cancer Research, 7, 171–179.

    Article  PubMed  CAS  Google Scholar 

  40. Ratsch, S. B., Gao, Q., Srinivasan, S., Wazer, D. E., & Band, V. (2001). Multiple genetic changes are required for efficient immortalization of different subtypes of normal human mammary epithelial cells. Radiation Research, 155, 143–150.

    Article  PubMed  CAS  Google Scholar 

  41. Li, Y., Pan, J., Li, J. L., Lee, J. H., Tunkey, C., Saraf, K., et al (2007). Transcriptional changes associated with breast cancer occur as normal human mammary epithelial cells overcome senescence barriers and become immortalized. Molecular Cancer, 6, 7.

    Article  PubMed  CAS  Google Scholar 

  42. Goodell, M. A., Brose, K., Paradis, G., Conner, A. S., & Mulligan, R. C. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. Journal of Experimental Medicine, 183, 1797–1806.

    Article  PubMed  CAS  Google Scholar 

  43. Spangrude, G. J., Klein, J., Heimfeld, S., Aihara, Y., & Weissman, I. L. (1989). Two monoclonal antibodies identify thymic-repopulating cells in mouse bone marrow. Journal of Immunology, 142, 425–430.

    CAS  Google Scholar 

  44. Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., et al. (2002). Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell, 109, 625–637.

    Article  PubMed  CAS  Google Scholar 

  45. Shen, Q., Goderie, S. K., Jin, L., Karanth, N., Sun, Y., Abramova, N., et al. (2004). Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science, 304, 1338–1340.

    Article  PubMed  CAS  Google Scholar 

  46. Farnie, G., Clarke, R. B., Spence, K., Pinnock, N., Brennan, K., Anderson, N. G., et al (2007). Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. Journal of the National Cancer Institute, 99, 616–627.

    Article  PubMed  CAS  Google Scholar 

  47. Clayton, H., Titley, I., & Vivanco, M. (2004). Growth and differentiation of progenitor/stem cells derived from the human mammary gland. Experimental Cell Research, 297, 444–460.

    Article  PubMed  CAS  Google Scholar 

  48. Nishimura, E., K. Jordan, S. A., Oshima, H., Yoshida, H.,Osawa, M., Moriyama, M., et al (2002). Dominant role of the niche in melanocyte stem-cell fate determination. Nature, 416, 854–860.

    Article  PubMed  CAS  Google Scholar 

  49. Mauro, A. (1961). Satellite cell of skeletal muscle fibers. Journal of Biophysical and Biochemical Cytology, 9, 493–495.

    Article  PubMed  CAS  Google Scholar 

  50. Collins, C. A., Olsen, I., Zammit, P. S., Heslop, L., Petrie, A., Partridge, T. A., et al. (2005). Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell, 122, 289–301.

    Article  PubMed  CAS  Google Scholar 

  51. Dreyfus, P. A., Chretien, F., Chazaud, B., Kirova, Y., Caramelle, P., Garcia, L., et al.(2004). Adult bone marrow-derived stem cells in muscle connective tissue and satellite cell niches. American Journal of Pathology, 164, 773–779.

    PubMed  Google Scholar 

  52. Ferrari, G., Cusella-De Angelis, G., Coletta, M., Paolucci, E., Stornaiuolo, A., Cossu, G., et al. San Raffaele-Telethon Institute for Gene Therapy, M. I. (1998). Muscle regeneration by bone marrow-derived myogenic progenitors. Science, 279, (5356), 1528–1530.

    Article  PubMed  CAS  Google Scholar 

  53. Fukada, S., Miyagoe-Suzuki, Y., Tsukihara, H., Yuasa, K., Higuchi, S., Ono, S., et al. Department of Immunology, G. S. o. P. S. O. U. S. O. J. (2002). Muscle regeneration by reconstitution with bone marrow or fetal liver cells from green fluorescent protein-gene transgenic mice. Journal of Cell Science, 115(Pt) 6, 1285–1293.

    PubMed  CAS  Google Scholar 

  54. LaBarge, M. A., Blau, H. M., Baxter Laboratory for Genetic Pharmacology, D. o. M., and Immunology, D. o. M. P. S. U. S. o. M. C. S. C. A. USA (2002). Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell, 111(4), 589–601.

    Article  PubMed  CAS  Google Scholar 

  55. Sherwood, R. I., Christensen, J. L., Conboy, I. M., Conboy, M. J., Rando, T. A., Weissman, I. L., et al (2004). Isolation of adult mouse myogenic progenitors: Functional heterogeneity of cells within and engrafting skeletal muscle. Cell, 119, 543–554.

    Article  PubMed  CAS  Google Scholar 

  56. Palermo, A. T., LaBarge, M. A., Doyonnas, R., Pomerantz, J., & Blau, H. M. (2005). Bone marrow contribution to skeletal muscle: A physiological response to stress. Developmental Biology, 279, 336–344.

    Article  PubMed  CAS  Google Scholar 

  57. Boulanger, C. A., Mack, D. L., Booth, B. W., & Smith, G. H. (2007). Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo. Proceedings of the National Academy of Sciences of the United States of America, 104, 3871–3876.

    Article  PubMed  CAS  Google Scholar 

  58. Scadden, D. T. (2006). The stem-cell niche as an entity of action. Nature, 441, 1075–1079.

    Article  PubMed  CAS  Google Scholar 

  59. Kai, T., & Spradling, A. (2003). An empty Drosophila stem cell niche reactivates the proliferation of ectopic cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 4633–4638.

    Article  PubMed  CAS  Google Scholar 

  60. Kai, T., & Spradling, A. (2004). Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature, 428, 564–569.

    Article  PubMed  CAS  Google Scholar 

  61. Bissell, M. J., & LaBarge, M. A. (2005). Context, tissue plasticity, and cancer: Are tumor stem cells also regulated by the microenvironment? Cancer Cell, 7, 17–23.

    PubMed  CAS  Google Scholar 

  62. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., & Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 3983–3988.

    Article  PubMed  CAS  Google Scholar 

  63. Weaver, V. M., Petersen, O. W., Wang, F., Larabell, C. A., Briand, P., Damsky, C., et al. (1997). Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. Journal of Cell Biology, 137, 231–245.

    Article  PubMed  CAS  Google Scholar 

  64. Tallman, M. S. Nabhan, C. Feusner, J. H., & Rowe, J. M. (2002). Acute promyelocytic leukemia: Evolving therapeutic strategies. Blood, 99, 759–767.

    Article  PubMed  CAS  Google Scholar 

  65. Park, C. C., Zhang, H., Pallavicini, M., Gray, J. W., Baehner, F., Park, C. J., et al. (2006). Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo. Cancer Research, 66, 1526–1535.

    Article  PubMed  CAS  Google Scholar 

  66. Matsunaga, T., Takemoto, N., Sato, T., Takimoto, R., Tanaka, I., Fujimi, A., et al. (2003). Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Natural Medicines, 9, 1158–1165.

    Article  CAS  Google Scholar 

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Ackowledgments

This work was supported by the National Institute of Health (CA-64786 to MJB and OWP, CA-57621 to MJB), and by grants from the OBER office of the US Department of Energy (DE-AC03-76SF00098 and a Distinguished Fellow Award to MJB), and the US Department of Defense (an Innovator Award to MJB). MAL is supported by a postdoctoral fellowship from the American Cancer Society.

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  1. Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    Mark A. LaBarge & Mina J. Bissell

  2. The Panum Institute, Copenhagen, Denmark

    Ole W. Petersen

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  1. Mark A. LaBarge
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Correspondence to Mark A. LaBarge or Mina J. Bissell.

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LaBarge, M.A., Petersen, O.W. & Bissell, M.J. Of Microenvironments and Mammary Stem Cells. Stem Cell Rev 3, 137–146 (2007). https://doi.org/10.1007/s12015-007-0024-4

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