Breast Cancer Stem Cells

  • Bert Gold
  • Michael Dean


One aspect of the analogy between embryogenesis and cancer is the emphasis on rapid cell division and self-renewal from a small number of immortal cells. A key understanding in developmental biology is the concept of determination and its consequences, in the form of lineage totipotency, pluripotency, multipotency, and unipotency. The normal cell fate decision point involves epigenetic mechanisms that are dysregulated in neoplasia. These dysregulated cell proliferation triggers are posited to specifically distinguish tumor-initiating cells from their progeny. Herein we present a review of the embryogenesis of the human breast, with an emphasis on the endocrine and epithelial–mesenchyme interactions required for proper development of tissues in the niche. We expand our conceptualization to include the relationship to the seed and soil hypothesis, and immunoediting theory. We expand on the new paradigm by explaining the relevance of side populations, plating efficiency, and tumor-initiating cells to cancer stem cell theory. Finally, we provide some suggestions for signal transduction pathway interventions, viz., that of the hedgehog/patched pathway, that might make breast cancer more amenable to specific therapeutic interventions.


Stem Cell Cancer Stem Cell Familial Adenomatous Polyposis Basal Cell Carcinoma Side Population 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors wish to thank Dr. Jodie Fleming of NCI, for her helpful comments on this chapter. This chapter has been funded in whole or in part with Federal Funds from the Center for Cancer Research, National Cancer Institute and the National Institutes of Health.


  1. Alberts, B. (2008). “Molecular biology of the cell. Reference edition.” Garland Science, New York.Google Scholar
  2. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., and Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100, 3983–8.PubMedGoogle Scholar
  3. Alley, M. C., Scudiero, D. A., Monks, A., Hursey, M. L., Czerwinski, M. J., Fine, D. L., Abbott, B. J., Mayo, J. G., Shoemaker, R. H., and Boyd, M. R. (1988). Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48, 589–601.PubMedGoogle Scholar
  4. Alonso, L., and Fuchs, E. (2003). Stem cells in the skin: waste not, Wnt not. Genes Dev 17, 1189–200.PubMedGoogle Scholar
  5. Ameryckx, L., Leunen, M., Wylock, P., and Amy, J. J. (2005). Breast problems in children and adolescents. Eur Clin Obstet Gynaecol 1, 151–63.Google Scholar
  6. Athar, M., Li, C., Tang, X., Chi, S., Zhang, X., Kim, A. L., Tyring, S. K., Kopelovich, L., Hebert, J., Epstein, E. H., Jr., Bickers, D. R., and Xie, J. (2004). Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res 64, 7545–52.PubMedGoogle Scholar
  7. Auersperg, N., Wong, A. S., Choi, K. C., Kang, S. K., and Leung, P. C. (2001). Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev 22, 255–88.PubMedGoogle Scholar
  8. Bale, A. E., and Yu, K. P. (2001). The hedgehog pathway and basal cell carcinomas. Hum Mol Genet 10, 757–62.PubMedGoogle Scholar
  9. Bapat, S. A. (2007). Evolution of cancer stem cells. Semin Cancer Biol 17, 204–13.PubMedGoogle Scholar
  10. Barnhart, B. C., and Simon, M. C. (2007). Metastasis and stem cell pathways. Cancer Metastasis Rev 26, 261–71.PubMedGoogle Scholar
  11. Bates, S. E., Mickley, L. A., Chen, Y. N., Richert, N., Rudick, J., Biedler, J. L., and Fojo, A. T. (1989). Expression of a drug resistance gene in human neuroblastoma cell lines: modulation by retinoic acid-induced differentiation. Mol Cell Biol 9, 4337–44.PubMedGoogle Scholar
  12. Beachy, P. A., Karhadkar, S. S., and Berman, D. M. (2004). Tissue repair and stem cell renewal in carcinogenesis. Nature 432, 324–31.PubMedGoogle Scholar
  13. Bengochea, A., de Souza, M. M., Lefrancois, L., Le Roux, E., Galy, O., Chemin, I., Kim, M., Wands, J. R., Trepo, C., Hainaut, P., Scoazec, J. Y., Vitvitski, L., and Merle, P. (2008). Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma. Br J Cancer 99, 143–50.PubMedGoogle Scholar
  14. Ben-Porath, I., Thomson, M. W., Carey, V. J., Ge, R., Bell, G. W., Regev, A., and Weinberg, R. A. (2008). An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40, 499–507.PubMedGoogle Scholar
  15. Berman, D. M., Karhadkar, S. S., Maitra, A., Montes De Oca, R., Gerstenblith, M. R., Briggs, K., Parker, A. R., Shimada, Y., Eshleman, J. R., Watkins, D. N., and Beachy, P. A. (2003). Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425, 846–51.PubMedGoogle Scholar
  16. Bijlsma, M. F., Spek, C. A., Zivkovic, D., van de Water, S., Rezaee, F., and Peppelenbosch, M. P. (2006). Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol 4, e232.PubMedGoogle Scholar
  17. Bjerknes, M. (1996). Expansion of mutant stem cell populations in the human colon. J Theor Biol 178, 381–5.PubMedGoogle Scholar
  18. Black, R. F., Jarman, L., and Simpson, J. (1998). “Lactation specialist self-study series.” Jones and Bartlett, Sudbury, MA.Google Scholar
  19. Blanpain, C., Horsley, V., and Fuchs, E. (2007). Epithelial stem cells: turning over new leaves. Cell 128, 445–58.PubMedGoogle Scholar
  20. Brinster, R. L. (1976). Participation of teratocarcinoma cells in mouse embryo development. Cancer Res 36, 3412–4.PubMedGoogle Scholar
  21. Brinton, R. D. (2001). Cellular and molecular mechanisms of estrogen regulation of memory function and neuroprotection against Alzheimer's disease: recent insights and remaining challenges. Learn Mem 8, 121–33.PubMedGoogle Scholar
  22. Buhimschi, C. S. (2004). Endocrinology of lactation. Obstet Gynecol Clin North Am 31, 963–79, xii.PubMedGoogle Scholar
  23. Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U., and Nishizuka, Y. (1982). Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 257, 7847–51.PubMedGoogle Scholar
  24. Chen, J. K., Taipale, J., Young, K. E., Maiti, T., and Beachy, P. A. (2002). Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA 99, 14071–6.PubMedGoogle Scholar
  25. Chidambaram, A., Goldstein, A. M., Gailani, M. R., Gerrard, B., Bale, S. J., DiGiovanna, J. J., Bale, A. E., and Dean, M. (1996). Mutations in the human homolog of the Drosophila patched gene in Caucasian and African American nevoid basal cell carcinoma syndrome patients. Cancer Res. 56, 4599–601.PubMedGoogle Scholar
  26. Chlebowski, R. T. (2005). Obesity and early-stage breast cancer. J Clin Oncol 23, 1345–7.PubMedGoogle Scholar
  27. Chung, L. W., Baseman, A., Assikis, V., and Zhau, H. E. (2005). Molecular insights into prostate cancer progression: the missing link of tumor microenvironment. J Urol 173, 10–20.PubMedGoogle Scholar
  28. Clarke, R. B. (2003). Steroid receptors and proliferation in the human breast. Steroids 68, 789–94.PubMedGoogle Scholar
  29. Cooper, A. (1840). “On the anatomy of the breast.” Longman, Orme, Green, Brown, and Longmans, London.Google Scholar
  30. Crawford, N. P., and Hunter, K. W. (2006). New perspectives on hereditary influences in metastatic progression. Trends Genet 22, 555–61.PubMedGoogle Scholar
  31. Creasy, R. K., Resnik, R., and Iams, J. D. (2004). “Maternal–fetal medicine : principles and practice.” Saunders, Philadelphia, PA.Google Scholar
  32. Dean, M. (1997). Towards a unified model of tumor suppression: lessons learned from the human patched gene. Biochim Biophys Acta 1332, M43–52.PubMedGoogle Scholar
  33. Dean, M., and Annilo, T. (2005). Evolution of the ATP-binding cassette (ABC) transporter superfamily in vertebrates. Annu Rev Genom Hum Genet 6, 123–42.Google Scholar
  34. Dean, M., Fojo, T., and Bates, S. (2005). Tumour stem cells and drug resistance. Nat Rev Cancer 5, 275–84.PubMedGoogle Scholar
  35. Deroo, B. J., and Korach, K. S. (2006). Estrogen receptors and human disease. J Clin Invest 116, 561–70.PubMedGoogle Scholar
  36. Deschner, E. E., and Lipkin, M. (1975). Proliferative patterns in colonic mucosa in familial polyposis. Cancer 35, 413–8.PubMedGoogle Scholar
  37. Deugnier, M. A., Faraldo, M. M., Janji, B., Rousselle, P., Thiery, J. P., and Glukhova, M. A. (2002). EGF controls the in vivo developmental potential of a mammary epithelial cell line possessing progenitor properties. J Cell Biol 159, 453–63.PubMedGoogle Scholar
  38. Do, J. T., Han, D. W., and Scholer, H. R. (2006). Reprogramming somatic gene activity by fusion with pluripotent cells. Stem Cell Rev 2, 257–64.PubMedGoogle Scholar
  39. Dontu, G., Al-Hajj, M., Abdallah, W. M., Clarke, M. F., and Wicha, M. S. (2003). Stem cells in normal breast development and breast cancer. Cell Prolif 36 Suppl 1, 59–72.PubMedGoogle Scholar
  40. Dunn, G. P., Old, L. J., and Schreiber, R. D. (2004a). The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–48.PubMedGoogle Scholar
  41. Dunn, G. P., Old, L. J., and Schreiber, R. D. (2004b). The three Es of cancer immunoediting. Annu Rev Immunol 22, 329–60.PubMedGoogle Scholar
  42. Eaden, J. (2004). Review article: colorectal carcinoma and inflammatory bowel disease. Alim Pharmacol Ther 20 Suppl 4, 24–30.Google Scholar
  43. Eccles, S. A., and Welch, D. R. (2007). Metastasis: recent discoveries and novel treatment strategies. Lancet 369, 1742–57.PubMedGoogle Scholar
  44. Elenbaas, B., Spirio, L., Koerner, F., Fleming, M. D., Zimonjic, D. B., Donaher, J. L., Popescu, N. C., Hahn, W. C., and Weinberg, R. A. (2001). Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev 15, 50–65.PubMedGoogle Scholar
  45. Fan, X., Matsui, W., Khaki, L., Stearns, D., Chun, J., Li, Y. M., and Eberhart, C. G. (2006). Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66, 7445–52.PubMedGoogle Scholar
  46. Folkman, J. (2002). Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29, 15–8.PubMedGoogle Scholar
  47. Fuchs, E. (1882). Das Sarkom des Uvealtractus. Graefe's Arch Ophthalmol XII, 233.Google Scholar
  48. Gail, M. H., Brinton, L. A., Byar, D. P., Corle, D. K., Green, S. B., Schairer, C., and Mulvihill, J. J. (1989). Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81, 1879–86.PubMedGoogle Scholar
  49. Gailani, M. R., Stahle-Backdahl, M., Leffell, D. J., Glynn, M., Zaphiropoulos, P. G., Pressman, C., Unden, A. B., Dean, M., Brash, D. E., Bale, A. E., and Toftgard, R. (1996). The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 14, 78–81.PubMedGoogle Scholar
  50. Gardner, E. J. (1962). Follow-up study of a family group exhibiting dominant inheritance for a syndrome including intestinal polyps, osteomas, fibromas and epidermal cysts. Am J Hum Genet 14, 376–90.PubMedGoogle Scholar
  51. Gilbert, S. F., Singer, S. R., Tyler, M. S., and Kozlowski, R. N. (2006). “Developmental biology.” Sinauer Associates, Sunderland, MA.Google Scholar
  52. Goodell, M. A., Brose, K., Paradis, G., Conner, A. S., and Mulligan, R. C. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183, 1797–806.PubMedGoogle Scholar
  53. Gottesman, M. M., Fojo, T., and Bates, S. E. (2002). Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2, 48–58.PubMedGoogle Scholar
  54. Groden, J., et al. (1991). Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589–600.PubMedGoogle Scholar
  55. Gupta, G. P., and Massague, J. (2006). Cancer metastasis: building a framework. Cell 127, 679–95.PubMedGoogle Scholar
  56. Hahn, H., Christiansen, J., Wicking, C., Zaphiropoulos, P. G., Chidambaram, A., Gerrard, B., Vorechovsky, I., Bale, A. E., Toftgard, R., Dean, M., and Wainwright, B. (1996a). A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental anomalies. J Biol Chem 271, 12125–8.PubMedGoogle Scholar
  57. Hahn, H., Wicking, C., Zaphiropoulous, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., and Bale, A. E. (1996b). Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–51.PubMedGoogle Scholar
  58. Hall, J. G. (2003). Twinning. Lancet 362, 735–43.PubMedGoogle Scholar
  59. Hamburger, A. W., and Salmon, S. E. (1977). Primary bioassay of human tumor stem cells. Science 197, 461–3.PubMedGoogle Scholar
  60. Harrison, R. F., and Biswas, S. (1980). Maternal plasma, human placental lactogen, alpha-fetoprotein, prolactin and growth hormone in early pregnancy. Int J Gynaecol Obstet 17, 471–6.PubMedGoogle Scholar
  61. Hemmati, H. D., Nakano, I., Lazareff, J. A., Masterman-Smith, M., Geschwind, D. H., Bronner-Fraser, M., and Kornblum, H. I. (2003). Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100, 15178–83.PubMedGoogle Scholar
  62. Hennings, H., and Boutwell, R. K. (1970). Studies on the mechanism of skin tumor promotion. Cancer Res 30, 312–20.PubMedGoogle Scholar
  63. Henrich, C. J., Bokesch, H. R., Dean, M., Bates, S. E., Robey, R. W., Goncharova, E. I., Wilson, J. A., and McMahon, J. B. (2006). A high-throughput cell-based assay for inhibitors of ABCG2 activity. J Biomol Screen 11, 176–83.PubMedGoogle Scholar
  64. Hewitt, R. E., McMarlin, A., Kleiner, D., Wersto, R., Martin, P., Tsokos, M., Stamp, G. W., and Stetler-Stevenson, W. G. (2000). Validation of a model of colon cancer progression. J Pathol 192, 446–54.PubMedGoogle Scholar
  65. Hirschmann-Jax, C., Foster, A. E., Wulf, G. G., Nuchtern, J. G., Jax, T. W., Gobel, U., Goodell, M. A., and Brenner, M. K. (2004). A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 101, 14228–33.PubMedGoogle Scholar
  66. Ho, K. J., and Liao, J. K. (2002). Nonnuclear actions of estrogen. Arterioscler Thromb Vasc Biol 22, 1952–61.PubMedGoogle Scholar
  67. Houghton, P. J., Germain, G. S., Harwood, F. C., Schuetz, J. D., Stewart, C. F., Buchdunger, E., and Traxler, P. (2004). Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res 64, 2333–7.PubMedGoogle Scholar
  68. Huang, X., Cho, S., and Spangrude, G. J. (2007). Hematopoietic stem cells: generation and self-renewal. Cell Death Differ 14, 1851–9.PubMedGoogle Scholar
  69. Ince, T. A., Richardson, A. L., Bell, G. W., Saitoh, M., Godar, S., Karnoub, A. E., Iglehart, J. D., and Weinberg, R. A. (2007). Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12, 160–70.PubMedGoogle Scholar
  70. Jaenisch, R., Hochedlinger, K., Blelloch, R., Yamada, Y., Baldwin, K., and Eggan, K. (2004). Nuclear cloning, epigenetic reprogramming, and cellular differentiation. Cold Spring Harb Symp Quant Biol 69, 19–27.PubMedGoogle Scholar
  71. James, L. F., Panter, K. E., Gaffield, W., and Molyneux, R. J. (2004). Biomedical applications of poisonous plant research. J Agric Food Chem 52, 3211–30.PubMedGoogle Scholar
  72. Jilka, R. L. (1998). Cytokines, bone remodeling, and estrogen deficiency: a 1998 update. Bone 23, 75–81.PubMedGoogle Scholar
  73. Johnson, R. L., Rothman, A. L., Xie, J., Goodrich, L. V., Bare, J. W., Bonifas, J. M., Quinn, A. G., Myers, R. M., Cox, D. R., Epstein, E. H., Jr., and Scott, M. P. (1996). Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–71.PubMedGoogle Scholar
  74. Jordan, V. C., and Morrow, M. (1999). Tamoxifen, raloxifene, and the prevention of breast cancer. Endocr Rev 20, 253–78.PubMedGoogle Scholar
  75. Karhadkar, S. S., Bova, G. S., Abdallah, N., Dhara, S., Gardner, D., Maitra, A., Isaacs, J. T., Berman, D. M., and Beachy, P. A. (2004). Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–12.PubMedGoogle Scholar
  76. Karpinets, T. V., and Foy, B. D. (2005). Tumorigenesis: the adaptation of mammalian cells to sustained stress environment by epigenetic alterations and succeeding matched mutations. Carcinogenesis 26, 1323–34.PubMedGoogle Scholar
  77. Kasemeier-Kulesa, J. C., Teddy, J. M., Postovit, L. M., Seftor, E. A., Seftor, R. E., Hendrix, M. J., and Kulesa, P. M. (2008). Reprogramming multipotent tumor cells with the embryonic neural crest microenvironment. Dev Dyn 237, 2657–2666.Google Scholar
  78. Kauff, N. D., Satagopan, J. M., Robson, M. E., Scheuer, L., Hensley, M., Hudis, C. A., Ellis, N. A., Boyd, J., Borgen, P. I., Barakat, R. R., Norton, L., Castiel, M., Nafa, K., and Offit, K. (2002). Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346, 1609–15.PubMedGoogle Scholar
  79. Kim, M., Turnquist, H., Jackson, J., Sgagias, M., Yan, Y., Gong, M., Dean, M., Sharp, J. G., and Cowan, K. (2002). The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res 8, 22–8.PubMedGoogle Scholar
  80. Kimball, J. W. (2003). Kimball's biology pages. John W. Kimball [Andover, MA].Google Scholar
  81. Kinzler, K. W., and Vogelstein, B. (1996). Lessons from hereditary colorectal cancer. Cell 87, 159–70.PubMedGoogle Scholar
  82. Knudson, A. G., Jr. (1971). Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68, 820–3.PubMedGoogle Scholar
  83. Knudson, A. G. (1993). Antioncogenes and human cancer. Proc Natl Acad Sci USA 90, 10914–21.PubMedGoogle Scholar
  84. Kondo, T., Setoguchi, T., and Taga, T. (2004). Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 101, 781–6.PubMedGoogle Scholar
  85. Kuperwasser, C., Chavarria, T., Wu, M., Magrane, G., Gray, J. W., Carey, L., Richardson, A., and Weinberg, R. A. (2004). Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci USA 101, 4966–71.PubMedGoogle Scholar
  86. LaBarge, M. A., Petersen, O. W., and Bissell, M. J. (2007). Of microenvironments and mammary stem cells. Stem Cell Rev 3, 137–46.PubMedGoogle Scholar
  87. Lagasse, E., Connors, H., Al-Dhalimy, M., Reitsma, M., Dohse, M., Osborne, L., Wang, X., Finegold, M., Weissman, I. L., and Grompe, M. (2000). Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6, 1229–34.PubMedGoogle Scholar
  88. Langley, R. R., and Fidler, I. J. (2007). Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev 28, 297–321.PubMedGoogle Scholar
  89. Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., Minden, M., Paterson, B., Caligiuri, M. A., and Dick, J. E. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–8.PubMedGoogle Scholar
  90. Lawrence, R. A., and Lawrence, R. A. (1985). “Breastfeeding, a guide for the medical profession.” Mosby, St. Louis.Google Scholar
  91. Leri, A., Kajstura, J., and Anversa, P. (2005). Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 85, 1373–416.PubMedGoogle Scholar
  92. Leslie, K. K., and Lange, C. A. (2005). Breast cancer and pregnancy. Obstet Gynecol Clin North Am 32, 547–58.PubMedGoogle Scholar
  93. Lou, H., and Dean, M. (2007). Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene 26, 1357–60.PubMedGoogle Scholar
  94. McCullough, L. D., Alkayed, N. J., Traystman, R. J., Williams, M. J., and Hurn, P. D. (2001). Postischemic estrogen reduces hypoperfusion and secondary ischemia after experimental stroke. Stroke 32, 796–802.PubMedGoogle Scholar
  95. McKenzie, J. L., Gan, O. I., Doedens, M., Wang, J. C., and Dick, J. E. (2006). Individual stem cells with highly variable proliferation and self-renewal properties comprise the human hematopoietic stem cell compartment. Nat Immunol 7, 1225–33.PubMedGoogle Scholar
  96. McLachlan, J. A. (2001). Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals. Endocr Rev 22, 319–41.PubMedGoogle Scholar
  97. Michalopoulos, G. K. (2007). Liver regeneration. J Cell Physiol 213, 286–300.PubMedGoogle Scholar
  98. Mickley, L. A., Bates, S. E., Richert, N. D., Currier, S., Tanaka, S., Foss, F., Rosen, N., and Fojo, A. T. (1989). Modulation of the expression of a multidrug resistance gene (mdr-1/P-glycoprotein) by differentiating agents. J Biol Chem 264, 18031–40.PubMedGoogle Scholar
  99. Mintz, B., and Illmensee, K. (1975). Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 72, 3585–9.PubMedGoogle Scholar
  100. Mizoguchi, T., Yamada, K., Furukawa, T., Hidaka, K., Hisatsugu, T., Shimazu, H., Tsuruo, T., Sumizawa, T., and Akiyama, S. (1990). Expression of the MDR1 gene in human gastric and colorectal carcinomas. J Natl Cancer Inst 82, 1679–83.PubMedGoogle Scholar
  101. Moore, K. L., Persaud, T. V. N., Moore, K. L., and Moore, K. L. (1993). “Study guide and review manual of human embryology.” Saunders, Philadelphia.Google Scholar
  102. Morrison, S. J., Shah, N. M., and Anderson, D. J. (1997). Regulatory mechanisms in stem cell biology. Cell 88, 287–98.PubMedGoogle Scholar
  103. Moser, A. R., Dove, W. F., Roth, K. A., and Gordon, J. I. (1992). The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol 116, 1517–26.PubMedGoogle Scholar
  104. Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S. N., Barrera, J. L., Mohar, A., Verastegui, E., and Zlotnik, A. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–6.PubMedGoogle Scholar
  105. Murphy, P. M. (2001). Chemokines and the molecular basis of cancer metastasis. N Engl J Med 345, 833–5.PubMedGoogle Scholar
  106. Nakachi, K., Hayashi, T., Imai, K., and Kusunoki, Y. (2004). Perspectives on cancer immuno-epidemiology. Cancer Sci 95, 921–9.PubMedGoogle Scholar
  107. Nishisho, I., Nakamura, Y., Miyoshi, Y., Miki, Y., Ando, H., Horii, A., Koyama, K., Utsunomiya, J., Baba, S., and Hedge, P. (1991). Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665–9.PubMedGoogle Scholar
  108. Nishiyama, K., Shirahama, T., Yoshimura, A., Sumizawa, T., Furukawa, T., Ichikawa-Haraguchi, M., Akiyama, S., and Ohi, Y. (1993). Expression of the multidrug transporter, P-glycoprotein, in renal and transitional cell carcinomas. Cancer 71, 3611–9.PubMedGoogle Scholar
  109. Norbury, R., Cutter, W. J., Compton, J., Robertson, D. M., Craig, M., Whitehead, M., and Murphy, D. G. (2003). The neuroprotective effects of estrogen on the aging brain. Exp Gerontol 38, 109–17.PubMedGoogle Scholar
  110. Novaro, V., Roskelley, C. D., and Bissell, M. J. (2003). Collagen-IV and laminin-1 regulate estrogen receptor alpha expression and function in mouse mammary epithelial cells. J Cell Sci 116, 2975–86.PubMedGoogle Scholar
  111. Novaro, V., Radisky, D. C., Ramos Castro, N. E., Weisz, A., and Bissell, M. J. (2004). Malignant mammary cells acquire independence from extracellular context for regulation of estrogen receptor alpha. Clin Cancer Res 10, 402S–9S.PubMedGoogle Scholar
  112. Nusslein-Volhard, C., and Wieschaus, E. (1980). Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801.PubMedGoogle Scholar
  113. Paget, S. (1889). The distribution of secondary growths in cancer of the breast. Lancet 133, 571–3.Google Scholar
  114. Parmar, H., and Cunha, G. R. (2004). Epithelial–stromal interactions in the mouse and human mammary gland in vivo. Endocr Relat Cancer 11, 437–58.PubMedGoogle Scholar
  115. Potten, C. S. (1991). Regeneration in epithelial proliferative units as exemplified by small intestinal crypts. CIBA Found Symp 160, 54–71; discussion 71–6.PubMedGoogle Scholar
  116. Raff, M. (2003). Adult stem cell plasticity: fact or artifact? Annu Rev Cell Dev Biol 19, 1–22.PubMedGoogle Scholar
  117. Rajaraman, R., Guernsey, D. L., Rajaraman, M. M., and Rajaraman, S. R. (2006). Stem cells, senescence, neosis and self-renewal in cancer. Cancer Cell Int 6, 25.PubMedGoogle Scholar
  118. Rakoff-Nahoum, S. (2006). Why cancer and inflammation? Yale J Biol Med 79, 123–30.PubMedGoogle Scholar
  119. Reya, T., Morrison, S. J., Clarke, M. F., and Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature 414, 105–11.PubMedGoogle Scholar
  120. Riordan, J. (2005). “Breastfeeding and human lactation.” Jones and Bartlett, Sudbury, MA.Google Scholar
  121. Rossouw, J. E. (2000). Debate: The potential role of estrogen in the prevention of heart disease in women after menopause. Curr Control Trials Cardiovasc Med 1, 135–8.PubMedGoogle Scholar
  122. Rous, P. (1966). The challenge to man of the neoplastic cell. In “Nobel Lectures”, pp. v. Published for the Nobel Foundation by Elsevier, Amsterdam, NY.Google Scholar
  123. Rous, P., and Kidd, J. G. (1941). Conditional neoplasms and sub-threshold states. A study of the tar tumours of rabbits. J Exp Med 73, 365–89.PubMedGoogle Scholar
  124. Scharenberg, C. W., Harkey, M. A., and Torok-Storb, B. (2002). The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood 99, 507–12.PubMedGoogle Scholar
  125. Schatton, T., and Frank, M. H. (2008). Cancer stem cells and human malignant melanoma. Pigment Cell Melanoma Res 21, 39–55.PubMedGoogle Scholar
  126. Schlessinger, D., and Van Zant, G. (2001). Does functional depletion of stem cells drive aging? Mech Ageing Dev 122, 1537–53.PubMedGoogle Scholar
  127. Seydoux, G., and Braun, R. E. (2006). Pathway to totipotency: lessons from germ cells. Cell 127, 891–904.PubMedGoogle Scholar
  128. Shankaran, V., Ikeda, H., Bruce, A. T., White, J. M., Swanson, P. E., Old, L. J., and Schreiber, R. D. (2001). IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–11.PubMedGoogle Scholar
  129. Shipitsin, M., and Polyak, K. (2008). The cancer stem cell hypothesis: in search of definitions, markers, and relevance. Lab Invest 88, 459–63.PubMedGoogle Scholar
  130. Shubik, P. (2002). Reflections on the implications of multistage carcinogenesis for the nature of neoplasia. Food Chem Toxicol 40, 739–42.PubMedGoogle Scholar
  131. Smith, G. H. (2006). Mammary stem cells come of age, prospectively. Trends Mol Med 12, 287–9.PubMedGoogle Scholar
  132. Smith, G. H., and Boulanger, C. A. (2002). Mammary stem cell repertoire: new insights in aging epithelial populations. Mech Ageing Dev 123, 1505–19.PubMedGoogle Scholar
  133. Spemann, H. (1918). Über die Determination der ersten Organanlagen des Amphibienembryonen. Zool Jahr Suppl 15, 1–48.Google Scholar
  134. Sternlicht, M. D. (2006). Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis. Breast Cancer Res 8, 201.PubMedGoogle Scholar
  135. Stetler-Stevenson, W. G. (2001). The role of matrix metalloproteinases in tumor invasion, metastasis, and angiogenesis. Surg Oncol Clin North Am 10, 383–92, x.Google Scholar
  136. Stevenson, R. E., and Hall, J. G. (2006). “Human malformations and related anomalies.” Oxford University Press, Oxford.Google Scholar
  137. Strieter, R. M. (2001). Chemokines: not just leukocyte chemoattractants in the promotion of cancer. Nat Immunol 2, 285–6.PubMedGoogle Scholar
  138. Su, L. K., Kinzler, K. W., Vogelstein, B., Preisinger, A. C., Moser, A. R., Luongo, C., Gould, K. A., and Dove, W. F. (1992). Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–70.PubMedGoogle Scholar
  139. Teicher, B. A. (1994). Hypoxia and drug resistance. Cancer Metastasis Rev 13, 139–68.PubMedGoogle Scholar
  140. Tennant, R. (1999). What is a tumor promoter? Environ Health Perspect 107, A390–1.Google Scholar
  141. Thayer, S. P., di Magliano, M. P., Heiser, P. W., Nielsen, C. M., Roberts, D. J., Lauwers, G. Y., Qi, Y. P., Gysin, S., Fernandez-del Castillo, C., Yajnik, V., Antoniu, B., McMahon, M., Warshaw, A. L., and Hebrok, M. (2003). Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–6.PubMedGoogle Scholar
  142. Thomlinson, R. H., and Gray, L. H. (1955). The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9, 539–49.PubMedGoogle Scholar
  143. Till, J. E., McCulloch, E. A., and Siminovitch, L. (1964). A stochastic model of stem cell proliferation, based on the growth of spleen colony-forming cells. Proc Natl Acad Sci USA 51, 29–36.PubMedGoogle Scholar
  144. Tostar, U., Malm, C.J., Meis-Kindblom, J.M., Kindblom, L. G., Toftgard, R., and Unden, A. B. (2006). Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol 208, 17–25.Google Scholar
  145. Trichopoulos, D., Lagiou, P., and Adami, H. O. (2005). Towards an integrated model for breast cancer etiology: the crucial role of the number of mammary tissue-specific stem cells. Breast Cancer Res 7, 13–7.PubMedGoogle Scholar
  146. Trosko, J. E. (2005). The role of stem cells and cell-cell communication in radiation carcinogenesis: ignored concepts. BJR Suppl 27, 132–8.PubMedGoogle Scholar
  147. Trosko, J. E., and Tai, M. H. (2006). Adult stem cell theory of the multi-stage, multi-mechanism theory of carcinogenesis: role of inflammation on the promotion of initiated stem cells. Contrib Microbiol 13, 45–65.PubMedGoogle Scholar
  148. Tsonis, P. A. (2007). Bridging knowledge gaps on the long road to regeneration: classical models meet stem cell manipulation and bioengineering. Mol Interv 7, 249–50.PubMedGoogle Scholar
  149. Vogelstein, B., and Kinzler, K. W. (1993). The multistep nature of cancer. Trends Genet 9, 138–41.PubMedGoogle Scholar
  150. Vona-Davis, L., and Rose, D. P. (2007). Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 14, 189–206.PubMedGoogle Scholar
  151. Waddington, C. H. (1966). “Principles of development and differentiation.” Macmillan, London.Google Scholar
  152. Ward, R. J., and Dirks, P. B. (2007). Cancer stem cells: at the headwaters of tumor development. Annu Rev Pathol 2, 175–89.PubMedGoogle Scholar
  153. Watkins, D. N., Berman, D. M., Burkholder, S. G., Wang, B., Beachy, P. A., and Baylin, S. B. (2003). Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422, 313–7.PubMedGoogle Scholar
  154. Xiao, Y., Ye, Y., Yearsley, K., Jones, S., and Barsky, S. H. (2008). The lymphovascular embolus of inflammatory breast cancer expresses a stem cell-like phenotype. Am J Pathol 173, 561–74.PubMedGoogle Scholar
  155. Zhai, P., Eurell, T. E., Cooke, P. S., Lubahn, D. B., and Gross, D. R. (2000a). Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and wild-type mice. Am J Physiol Heart Circ Physiol 278, H1640–7.Google Scholar
  156. Zhai, P., Eurell, T. E., Cotthaus, R., Jeffery, E. H., Bahr, J. M., and Gross, D. R. (2000b). Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats. Am J Physiol Heart Circ Physiol 279, H2766–75.Google Scholar
  157. Zhou, S., Schuetz, J. D., Bunting, K. D., Colapietro, A. M., Sampath, J., Morris, J. J., Lagutina, I., Grosveld, G. C., Osawa, M., Nakauchi, H., and Sorrentino, B. P. (2001). The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7, 1028–34.PubMedGoogle Scholar
  158. Zhou, S., Morris, J. J., Barnes, Y., Lan, L., Schuetz, J. D., and Sorrentino, B. P. (2002). Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. Proc Natl Acad Sci USA 99, 12339–44.PubMedGoogle Scholar
  159. Zimonjic, D., Brooks, M. W., Popescu, N., Weinberg, R. A., and Hahn, W. C. (2001). Derivation of human tumor cells in vitro without widespread genomic instability. Cancer Res 61, 8838–44.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Human Genetics Section, Laboratory of Experimental ImmunologyCancer Inflammation Program, Center for Cancer Research, NCI-FrederickFrederickUSA

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