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Mammary Stem Cells and Breast Cancer—Role of Notch Signalling

Stem Cell Reviews volume 3, pages 169–175 (2007)Cite this article

Abstract

Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44+/CD24− and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A γ-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.

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References

  1. Morrison, S. J., Shah, N. M., & Anderson, D. J. (1997). Regulatory mechanisms in stem cell biology. Cell, 88(3), 287–298.

    PubMed  Article  CAS  Google Scholar 

  2. Weissman, I. L. (2000). Stem cells: units of development, units of regeneration, and units in evolution. Cell, 100(1), 157–168.

    PubMed  Article  CAS  Google Scholar 

  3. 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(5), 515–520.

    PubMed  CAS  Google Scholar 

  4. Hoshino, K., & Gardner, W. U. (1967). Transplantability and life span of mammary gland during serial transplantation in mice. Nature, 213(5072), 193–194.

    PubMed  Article  CAS  Google Scholar 

  5. Daniel, C. W., De Ome, K. B., Young, J. T., Blair, P. B., & Faulkin, L. J., Jr. (1968). The in vivo life span of normal and preneoplastic mouse mammary glands: A serial transplantation study. Proceedings of the National Academy of Sciences of the United States of America, 61(1), 53–60.

    PubMed  Article  CAS  Google Scholar 

  6. Ormerod, E. J., & Rudland, P. S. (1986). Regeneration of mammary glands in vivo from isolated mammary ducts. Journal of Embryology and Experimental Morphology, 96, 229–243.

    PubMed  CAS  Google Scholar 

  7. Novelli, M., Cossu, A., Oukrif, D., Quaglia, A., Lakhani, S., Poulsom, R., et al. (2003). X-inactivation patch size in human female tissue confounds the assessment of tumor clonality. Proceedings of the National Academy of Sciences of the United States of America, 100(6), 3311–3314.

    PubMed  Article  CAS  Google Scholar 

  8. 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(2), 402–404.

    PubMed  CAS  Google Scholar 

  9. 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. Developments in Biologicals, 245(1), 42–56.

    CAS  Google Scholar 

  10. Clarke, R. B., Spence, K., Anderson, E., Howell, A., Okano, H., & Potten, C. S. (2005). A putative human breast stem cell population is enriched for steroid receptor-positive cells. Developments in Biologicals, 277(2), 443–456.

    CAS  Google Scholar 

  11. Clayton, H., Titley, I., & Vivanco, M. (2004). Growth and differentiation of progenitor/stem cells derived from the human mammary gland. Experimental Cell Research, 297(2), 444–460.

    PubMed  Article  CAS  Google Scholar 

  12. Alvi, A. J., Clayton, H., Joshi, C., Enver, T., Ashworth, A., Vivanco, M. M., et al. (2003). Functional and molecular characterisation of mammary side population cells. Breast Cancer Research, 5(1), R1–R8.

    PubMed  Article  Google Scholar 

  13. Dontu, G., Abdallah, W. M., Foley, J. M., Jackson, K. W., Clarke, M. F., Kawamura, M. J., et al. (2003). In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes & Development, 17(10), 1253–1270.

    Article  CAS  Google Scholar 

  14. Goodell, M. A., Rosenzweig, M., Kim, H., Marks, D. F., DeMaria, M., Paradis, G., et al. (1997). Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Natural Medicines, 3(12), 1337–1345.

    Article  CAS  Google Scholar 

  15. 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(7072), 84–88.

    PubMed  Article  CAS  Google Scholar 

  16. Stingl, J., Eirew, P., Ricketson, I., Shackleton, M., Vaillant, F., Choi, D., et al. (2006). Purification and unique properties of mammary epithelial stem cells. Nature, 439(7079), 993–997.

    PubMed  CAS  Google Scholar 

  17. Pardal, R., Clarke, M. F., & Morrison, S. J. (2003). Applying the principles of stem-cell biology to cancer. Nature Reviews Cancer, 3(12), 895–902.

    PubMed  Article  CAS  Google Scholar 

  18. Dontu, G., Al-Hajj M., Abdallah, W. M., Clarke, M. F., & Wicha, M. S. (2003). Stem cells in normal breast development and breast cancer. Cell Proliferation, 36(Suppl 1), 59–72.

    PubMed  Article  CAS  Google Scholar 

  19. Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105–111.

    PubMed  Article  CAS  Google Scholar 

  20. Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3(7), 730–737.

    PubMed  Article  CAS  Google Scholar 

  21. Ignatova, T. N., Kukekov, V. G., Laywell, E. D., Suslov, O. N., Vrionis, F. D., & Steindler, D. A. (2002). Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia, 39(3), 193–206.

    PubMed  Article  Google Scholar 

  22. Singh, S. K., Clarke, I. D., Terasaki, M., Bonn, V. E., Hawkins, C., Squire, J., et al. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Research, 63(18), 5821–5828.

    PubMed  CAS  Google Scholar 

  23. Singh, S. K., Hawkins, C., Clarke, I. D., Squire, J. A., Bayani, J., Hide, T., et al.. (2004). Identification of human brain tumour initiating cells. Nature, 432(7015), 396–401.

    PubMed  Article  CAS  Google Scholar 

  24. Hemmati, H. D., Nakano, I., Lazareff, J. A., Masterman-Smith, M., Geschwind, D. H., & Bronner-Fraser, M., et al. (2003). Cancerous stem cells can arise from pediatric brain tumors. Proceedings of the National Academy of Sciences of the United States of America, 100(25), 15178–15183.

    PubMed  Article  CAS  Google Scholar 

  25. Collins, A. T., Berrym, P. A., Hyde, C., Stower, M. J., & Maitland, N. J. (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Research, 65(23), 10946–10951.

    PubMed  Article  CAS  Google Scholar 

  26. Lawson, D. A., Xin, L., Lukacs, R. U., Cheng, D., & Witte, O. N., (2007). Isolation and functional characterization of murine prostate stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104(1), 181–186.

    PubMed  Article  CAS  Google Scholar 

  27. Li, C., Heidt D. G., Dalerba P., Burant, C. F., Zhang, L., Adsay, V., et al. (2007). Identification of pancreatic cancer stem cells. Cancer Research, 67(3), 1030–1037.

    PubMed  Article  CAS  Google Scholar 

  28. O’Brien, C. A., Pollett, A., Gallinger, S., & Dick, J. E. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature, 445(7123), 106–110.

    PubMed  Article  CAS  Google Scholar 

  29. Ricci-Vitiani, L., Lombardi, D. G., Pilozzi, E., Biffoni, M., Todaro, M., Peschle, C., et al. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature, 445(7123), 111–115.

    PubMed  Article  CAS  Google Scholar 

  30. 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(7), 3983–3988.

    PubMed  Article  CAS  Google Scholar 

  31. Wang, J. C., & Dick, J. E. (2005). Cancer stem cells: Lessons from leukemia. Trends in Cell Biology, 15(9), 494–501.

    PubMed  Article  CAS  Google Scholar 

  32. Ponti, D., Costam, A., Zaffaroni, N., Pratesi, G., Petrangolini, G., Coradini, D., et al. (2005). Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Research, 65(13), 5506–5511.

    PubMed  Article  CAS  Google Scholar 

  33. Patrawala, L., Calhoun, T., Schneider-Broussard, R., Zhou, J., Claypool, K., & Tang, D. G. (2005). Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Research, 65(14), 6207–6219.

    PubMed  Article  CAS  Google Scholar 

  34. Woodward, W. A., Chen, M. S., Behbod, F., Alfaro, M. P., Buchholz, T. A., & Rosen, J. M. (2007). WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 104(2), 618–663.

    PubMed  Article  CAS  Google Scholar 

  35. Phillips, T. M., McBride, W. H., & Pajonk, F. (2006). The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. Journal of the National Cancer Institute, 98(24), 1777–1785.

    PubMed  Article  Google Scholar 

  36. Bao, S., Wu, Q., McLendon, R. E., Hao, Y., Shi, Q., Hjelmeland, A. B., et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444(7120), 756–760.

    PubMed  Article  CAS  Google Scholar 

  37. Liu, B. Y., McDermott, S. P., Khwaja, S. S., & Alexander, C. M. (2004). The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 101(12), 4158–4163.

    PubMed  Article  CAS  Google Scholar 

  38. Li, Y., Welm, B., Podsypanina, K., Huang, S., Chamarro, M., Zhang, X., et al. (2003). Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 100(26), 15853–15858.

    PubMed  Article  CAS  Google Scholar 

  39. Dontu, G., Wicha, M. S. (2005). Survival of mammary stem cells in suspension culture: implications for stem cell biology and neoplasia. Journal of Mammary Gland Biology and Neoplasia, 10(1), 75–86.

    PubMed  Article  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  41. Stylianou, S., Clarke, R. B., & Brennan, K. (2006). Aberrant activation of notch signaling in human breast cancer. Cancer Research, 66(3), 1517–1525.

    PubMed  Article  CAS  Google Scholar 

  42. Kritikou, E. A., Sharkey, A., Abell, K., Came, P. J., Anderson, E., Clarkson, R. W., et al. (2003). A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland. Development, 130(15), 3459–3468.

    PubMed  Article  CAS  Google Scholar 

  43. Ewan, K. B., Oketch-Rabah, H. A., Ravani, S. A., Shyamala, G., Moses, H. L., & Barcellos-Hoff, M. H. (2005). Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice. American Journal of Pathology, 167(2), 409–417.

    PubMed  CAS  Google Scholar 

  44. 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(4), 552–560.

    PubMed  Article  CAS  Google Scholar 

  45. Lai, E. C. (2004). Notch signaling: Control of cell communication and cell fate. Development, 131(5), 965–973.

    PubMed  Article  CAS  Google Scholar 

  46. Politi, K., Feirt, N., & Kitajewski, J. (2004). Notch in mammary gland development and breast cancer. Seminars in Cancer Biology, 14(5), 341–347.

    PubMed  Article  CAS  Google Scholar 

  47. Nichols, J. T., Miyamoto, A., Olsen, S. L., D’Souza, B., Yao, C., & Weinmaster, G. (2007). DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. Journal of Cell Biology, 176(4), 445–458.

    PubMed  Article  CAS  Google Scholar 

  48. de la Pompa, J. L., Wakeham, A., Correia, K. M., Samper, E., Brown, S., Aguilera, R. J., et al. (1997). Conservation of the Notch signalling pathway in mammalian neurogenesis. Development, 124(6), 1139–1148.

    PubMed  Google Scholar 

  49. Ross, D. A., Rao, P. K., & Kadesch, T. (2004). Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes. Molecular and Cellular Biology, 24(8), 3505–3513.

    PubMed  Article  CAS  Google Scholar 

  50. Uyttendaele, H., Soriano, J. V., Montesano, R., & Kitajewski, J. (1998). Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion. Developments in Biologicals, 196(2), 204–217.

    CAS  Article  Google Scholar 

  51. Gallahan, D., Jhappan, C., Robinson, G., Hennighausen, L., Sharp, R., Kordon, E. et al. (1996). Expression of a truncated Int3 gene in developing secretory mammary epithelium specifically retards lobular differentiation resulting in tumorigenesis. Cancer Research, 56(8), 1775–1785.

    PubMed  CAS  Google Scholar 

  52. Smith, G. H., Gallahan, D., Diella, F., Jhappan, C., Merlino, G., & Callahan, R. (1995). Constitutive expression of a truncated INT3 gene in mouse mammary epithelium impairs differentiation and functional development. Cell Growth & Differentiation, 6(5), 563–577.

    CAS  Google Scholar 

  53. Jhappan, C., Gallahan, D., Stahle, C., Chu, E., Smith, G. H., Merlino, G., et al. (1992). Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes & Development, 6(3), 345–355.

    Article  CAS  Google Scholar 

  54. Pece, S., Serresi, M., Santolini, E., Capra, M., Hulleman, E., Galimberti, V., et al. (2004). Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. Journal of Cell Biology, 167(2), 215–221.

    PubMed  Article  CAS  Google Scholar 

  55. Reedijk, M., Odorcic, S., Chang, L., Zhang, H., Miller, N., McCready, D. R., et al. (2005). High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Research, 65(18), 8530–8537.

    PubMed  Article  CAS  Google Scholar 

  56. Sansone, P., Storci, G., Giovannini, C., Pandolfi, S., Pianetti, S., Taffurelli, M., et al. (2007). p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells, 25(3), 807–815.

    PubMed  Article  CAS  Google Scholar 

  57. Shipitsin, M., Campbell, L. L., Argani, P., Weremowicz, S., Bloushtain-Qimron, N., Yao, J., et al. (2007). Molecular definition of breast tumor heterogeneity. Cancer Cell, 11(3), 259–273.

    PubMed  Article  CAS  Google Scholar 

  58. 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 EGF receptor signaling pathways. Journal of the National Cancer Institute, 99(8), 616–627.

    PubMed  Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Breast Biology Group, Division of Cancer Studies, Faculty of Medicine and Human Sciences, University of Manchester, Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M20 4BX, UK

    Gillian Farnie & Robert B. Clarke

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  1. Gillian Farnie
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  2. Robert B. Clarke
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Correspondence to Robert B. Clarke.

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Farnie, G., Clarke, R.B. Mammary Stem Cells and Breast Cancer—Role of Notch Signalling. Stem Cell Rev 3, 169–175 (2007). https://doi.org/10.1007/s12015-007-0023-5

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Keywords

  • Cancer Stem Cell
  • Notch Signalling
  • Side Population
  • DAPT
  • Mammary Stem Cell