Are Stem-Like Cells Responsible for Resistance to Therapy in Breast Cancer?

  • Ciara S. O’Brien
  • Gillian Farnie
  • Sacha J. Howell
  • Robert B. Clarke

There is increasing evidence suggesting that some tumours originate from a stem cell population. Such observations appear to support the hypothesis that tumours can be generated and maintained by a small subset of undifferentiated cells able to self renew and differentiate into the bulk tumour population. Recently, cells with cancer stem cell-like properties have been identified within breast cancer tissues suggesting that a proportion of breast cancers may originate from such progenitors. Moreover, the intrinsic resistance of cancer stem cells (CSCs) to a range of chemotherapies suggests that their presence in breast cancer may also play a significant role in the development of an endocrine-resistant state. Future clarification of the role that CSCs play in such tumours, particularly in the context of therapeutic resistance, may lead to new treatment strategies for breast cancer where targeting of the CSCs specifically could lead to better and more sustained responses.


Breast Cancer stem cells Oestrogen receptor Endocrine therapy Resistance 


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  1. (EBCTCG), E.B.C.T.C.G. (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet, 365, 1687–1717.Google Scholar
  2. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., Clarke, M.F. (2003) From the cover: prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A, 100, 3983–3988.Google Scholar
  3. Arpino, G., Gutierrez, C., Weiss, H., Rimawi, M., Massarweh, S., Bharwani, L., De Placido, S., Osborne, C.K., Schiff, R. (2007) Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst, 99, 694–705.PubMedCrossRefGoogle Scholar
  4. Asselin-Labat, M.L., Shackleton, M., Stingl, J., Vaillant, F., Forrest, N.C., Eaves, C.J., Visvader, J.E., Lindeman, G.J. (2006) Steroid hormone receptor status of mouse mammary stem cells. J Natl Cancer Inst, 98, 1011–1014.PubMedGoogle Scholar
  5. Bao, S., Wu, Q., McLendon, R.E., Hao, Y., Shi, Q., Hjelmeland, A.B., Dewhirst, M.W., Bigner, D.D., Rich, J.N. (2006a) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444, 756–760.Google Scholar
  6. Bao, S., Wu, Q., Sathornsumetee, S., Hao, Y., Li, Z., Hjelmeland, A.B., Shi, Q., McLendon, R.E., Bigner, D.D., Rich, J.N. (2006b) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res, 66, 7843–7848.CrossRefGoogle Scholar
  7. Bar, E.E., Chaudhry, A., Lin, A., Fan, X., Schreck, K., Matsui, W., Piccirillo, S., Vescovi, A.L., DiMeco, F., Olivi, A., Eberhart, C.G. (2007) Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells, 25, 2524–2533.PubMedCrossRefGoogle Scholar
  8. Bonnet, D., Dick, J.E. (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med, 3, 730–737.PubMedCrossRefGoogle Scholar
  9. Calabrese, C., Poppleton, H., Kocak, M., Hogg, T.L., Fuller, C., Hamner, B., Oh, E.Y., Gaber, M.W., Finklestein, D., Allen, M., Frank, A., Bayazitov, I.T., Zakharenko, S.S., Gajjar, A., Davidoff, A., Gilbertson, R.J. (2007) A perivascular niche for brain tumor stem cells. Cancer Cell, 11, 69–82.PubMedCrossRefGoogle Scholar
  10. Clarke, M., Collins, R., Darby, S., Davies, C., Elphinstone, P., Evans, E., Godwin, J., Gray, R., Hicks, C., James, S., MacKinnon, E., McGale, P., McHugh, T., Peto, R., Taylor, C., Wang, Y. (2005a) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet, 366, 2087–2106.Google Scholar
  11. Clarke, R.B., Howell, A., Potten, C.S., Anderson, E. (1997) Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res, 57, 4987–4991.PubMedGoogle Scholar
  12. 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. Dev Biol, 277, 443–456.CrossRefGoogle Scholar
  13. Clayton, H., Titley, I., Vivanco, M. (2004) Growth and differentiation of progenitor/stem cells derived from the human mammary gland. Exp Cell Res, 297, 444–460.PubMedCrossRefGoogle Scholar
  14. Collins, A.T., Berry, P.A., Hyde, C., Stower, M.J., Maitland, N.J. (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res, 65, 10946–10951.PubMedCrossRefGoogle Scholar
  15. Dings, R.P., Loren, M., Heun, H., McNiel, E., Griffioen, A.W., Mayo, K.H., Griffin, R.J. (2007) Scheduling of radiation with angiogenesis inhibitors anginex and avastin improves therapeutic outcome via vessel normalization. Clin Cancer Res, 13, 3395–3402.PubMedCrossRefGoogle Scholar
  16. Fan, X., Matsui, W., Khaki, L., Stearns, D., Chun, J., Li, Y.M., Eberhart, C.G. (2006) Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res, 66, 7445–7452.PubMedCrossRefGoogle Scholar
  17. Farnie, G., Clarke, R.B., Spence, K., Pinnock, N., Brennan, K., Anderson, N.G., Bundred, N.J. (2007) Novel cell culture technique for primary ductal carcinoma in situ: role of notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst, 99, 616–627.PubMedCrossRefGoogle Scholar
  18. Fillmore, C.M., Kuperwasser, C. (2008) Human breast cancer cell lines contain stem-like cells with the capacity to self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res, 10, R25.PubMedCrossRefGoogle Scholar
  19. Folkins, C., Man, S., Xu, P., Shaked, Y., Hicklin, D.J., Kerbel, R.S. (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res, 67, 3560–3564.PubMedCrossRefGoogle Scholar
  20. Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., Fuks, Z., Kolesnick, R. (2003) Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science, 300, 1155–1159.PubMedCrossRefGoogle Scholar
  21. Ginestier, C., Hur, M.H., Charafe-Jauffret, E., Monville, F., Dutcher, J., Brown, M., Jacquemier, J., Viens, P., Kleer, C.G., Liu, S., Schott, A., Hayes, D., Birnbaum, D., Wicha, M.S., Dontu, G. (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 1, 555–567.PubMedCrossRefGoogle Scholar
  22. Guzman, R.C., Yang, J., Rajkumar, L., Thordarson, G., Chen, X., Nandi, S. (1999) Hormonal prevention of breast cancer: mimicking the protective effect of pregnancy. Proc Natl Acad Sci U S A, 96, 2520–2525.PubMedCrossRefGoogle Scholar
  23. Howell, A., Wardley, A.M. (2005) Overview of the impact of conventional systemic therapies on breast cancer. Endocr Relat Cancer, 12(Suppl 1), S9–S16.PubMedCrossRefGoogle Scholar
  24. Keith, B., Simon, M.C. (2007) Hypoxia-inducible factors, stem cells, and cancer. Cell, 129, 465–472.PubMedCrossRefGoogle Scholar
  25. Kozin, S.V., Winkler, F., Garkavtsev, I., Hicklin, D.J., Jain, R.K., Boucher, Y. (2007) Human tumor xenografts recurring after radiotherapy are more sensitive to anti-vascular endothelial growth factor receptor-2 treatment than treatment-naive tumors. Cancer Res, 67, 5076–5082.PubMedCrossRefGoogle Scholar
  26. Li, X., Lewis, M.T., Huang, J., Gutierrez, C., Osborne, C.K., Wu, M.F., Hilsenbeck, S.G., Pavlick, A., Chamness, G.C., Wong, H., Rosen, J., Chang, J.C. (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst, 100(9), 672–9.PubMedCrossRefGoogle Scholar
  27. Liby, K., Royce, D.B., Risingsong, R., Williams, C.R., Wood, M.D., Chandraratna, R.A., Sporn, M.B. (2007) A new rexinoid, NRX194204, prevents carcinogenesis in both the lung and mammary gland. Clin Cancer Res, 13, 6237–6243.PubMedCrossRefGoogle Scholar
  28. McClelland, R.A., Barrow, D., Madden, T.A., Dutkowski, C.M., Pamment, J., Knowlden, J.M., Gee, J.M., Nicholson, R.I. (2001) Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (faslodex). Endocrinology, 142, 2776–2788.PubMedCrossRefGoogle Scholar
  29. Miller, K., Wang, M., Gralow, J., Dickler, M., Cobleigh, M., Perez, E.A., Shenkier, T., Cella, D. (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med, 357, 2666–2676.PubMedCrossRefGoogle Scholar
  30. 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, 106–110.PubMedCrossRefGoogle Scholar
  31. Ohno, R., Asou, N., Ohnishi, K. (2003) Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate. Leukemia, 17, 1454–1463.PubMedCrossRefGoogle Scholar
  32. Osborne, C.K., Bardou, V., Hopp, T.A., Chamness, G.C., Hilsenbeck, S.G., Fuqua, S.A., Wong, J., Allred, D.C., Clark, G.M., Schiff, R. (2003) Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst, 95, 353–361.PubMedGoogle 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 Res, 65, 6207–6219.PubMedCrossRefGoogle Scholar
  34. Perou, C.M., Sorlie, T., Eisen, M.B., van de Rijn, M., Jeffrey, S.S., Rees, C.A., Pollack, J.R., Ross, D.T., Johnsen, H., Akslen, L.A., Fluge, O., Pergamenschikov, A., Williams, C., Zhu, S.X., Lonning, P.E., Borresen-Dale, A.L., Brown, P.O., Botstein, D. (2000) Molecular portraits of human breast tumours. Nature, 406, 747–752.PubMedCrossRefGoogle Scholar
  35. Phillips, T.M., McBride, W.H., Pajonk, F. (2006) The response of CD24(-low)CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst, 98, 1777–1785.PubMedCrossRefGoogle Scholar
  36. Piccirillo, S.G., Reynolds, B.A., Zanetti, N., Lamorte, G., Binda, E., Broggi, G., Brem, H., Olivi, A., Dimeco, F., Vescovi, A.L. (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature, 444, 761–765.PubMedCrossRefGoogle Scholar
  37. Ponti, D., Costa, A., Zaffaroni, N., Pratesi, G., Petrangolini, G., Coradini, D., Pilotti, S., Pierotti, M.A., Daidone, M.G. (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res, 65, 5506–5511.PubMedCrossRefGoogle Scholar
  38. Reya, T., Morrison, S.J., Clarke, M.F., Weissman, I.L. (2001) Stem cells, cancer, and cancer stem cells. Nature, 414, 105–111.PubMedCrossRefGoogle Scholar
  39. Ricci-Vitiani, L., Lombardi, D.G., Pilozzi, E., Biffoni, M., Todaro, M., Peschleand De Maria, C.R. (2007) Identification and expansion of human colon-cancer-initiating cells. Nature, 445, 111–115.PubMedCrossRefGoogle Scholar
  40. Seagroves, T.N., Lydon, J.P., Hovey, R.C., Vonderhaar, B.K., Rosen, J.M. (2000) C/EBPbeta (CCAAT/enhancer binding protein) controls cell fate determination during mammary gland development. Mol Endocrinol, 14, 359–368.PubMedCrossRefGoogle Scholar
  41. Shekhar, M.P., Santner, S., Carolin, K.A., Tait, L. (2007) Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am J Pathol, 170, 1546–1560.PubMedCrossRefGoogle Scholar
  42. Shoker, B.S., Jarvis, C., Clarke, R.B., Anderson, E., Hewlett, J., Davies, M.P., Sibson, D.R., Sloane, J.P. (1999) Estrogen receptor-positive proliferating cells in the normal and precancerous breast. Am J Pathol, 155, 1811–1815.PubMedGoogle Scholar
  43. Sims-Mourtada, J., Izzo, J.G., Ajani, J., Chao, K.S. (2007) Sonic hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene, 26, 5674–5679.PubMedCrossRefGoogle Scholar
  44. Sims-Mourtada, J., Izzo, J.G., Apisarnthanarax, S., Wu, T.T., Malhotra, U., Luthra, R., Liao, Z., Komaki, R., van der Kogel, A., Ajani, J., Chao, K.S. (2006) Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res, 12, 6565–6572.PubMedCrossRefGoogle Scholar
  45. Sims, A.H., Howell, A., Howell, S.J., Clarke, R.B. (2007) Origins of breast cancer subtypes and therapeutic implications. Nat Clin Pract Oncol, 4, 516–525.PubMedCrossRefGoogle Scholar
  46. Singh, S.K., Clarke, I.D., Terasaki, M., Bonn, V.E., Hawkins, C., Squire, J., Dirks, P.B. (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res, 63, 5821–5828.PubMedGoogle Scholar
  47. Singh, S.K., Hawkins, C., Clarke, I.D., Squire, J.A., Bayani, J., Hide, T., Henkelman, R.M., Cusimano, M.D., Dirks, P.B. (2004) Identification of human brain tumour initiating cells. Nature, 432, 396–401.PubMedCrossRefGoogle Scholar
  48. Sleeman, K.E., Kendrick, H., Robertson, D., Isacke, C.M., Ashworth, A., Smalley, M.J. (2007) Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. J Cell Biol, 176, 19–26.PubMedCrossRefGoogle Scholar
  49. Sorlie, T., Perou, C.M., Tibshirani, R., Aas, T., Geisler, S., Johnsen, H., Hastie, T., Eisen, M.B., van de Rijn, M., Jeffrey, S.S., Thorsen, T., Quist, H., Matese, J.C., Brown, P.O., Botstein, D., Eystein Lonning, P., Borresen-Dale, A.L. (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A, 98, 10869–10874.PubMedCrossRefGoogle Scholar
  50. Sorlie, T., Tibshirani, R., Parker, J., Hastie, T., Marron, J.S., Nobel, A., Deng, S., Johnsen, H., Pesich, R., Geisler, S., Demeter, J., Perou, C.M., Lonning, P.E., Brown, P.O., Borresen-Dale, A.L., Botstein, D. (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A, 100, 8418–8423.PubMedCrossRefGoogle Scholar
  51. Storms, R.W., Trujillo, A.P., Springer, J.B., Shah, L., Colvin, O.M., Ludeman, S.M., Smith, C. (1999) Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proc Natl Acad Sci U S A, 96, 9118–9123.PubMedCrossRefGoogle Scholar
  52. Todaro, M., Perez Alea, M., Di Stefano, A.B., Cammareri, P., Vermeulen, L., Iovino, F., Tripodo, C., Russo, A., Gulotta, G., Medema, J.P., Stassi, G. (2007) Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell, 1, 389–402.PubMedCrossRefGoogle Scholar
  53. Warri, A.M., Laine, A.M., Majasuo, K.E., Alitalo, K.K., Harkonen, P.L. (1991) Estrogen suppression of erbB2 expression is associated with increased growth rate of ZR-75-1 human breast cancer cells in vitro and in nude mice. Int J Cancer, 49, 616–623.PubMedCrossRefGoogle Scholar
  54. 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. Proc Natl Acad Sci U S A, 104, 618–623.PubMedCrossRefGoogle Scholar
  55. Wu, K., DuPre, E., Kim, H., Tin, U.C., Bissonnette, R.P., Lamph, W.W., Brown, P.H. (2006) Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade. Breast Cancer Res Treat, 96, 147–157.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Ciara S. O’Brien
  • Gillian Farnie
  • Sacha J. Howell
  • Robert B. Clarke
    • 1
  1. 1.Breast Biology Group School of Cancer and Imaging Sciences, Paterson Institute for Cancer ResearchUniversity of ManchesterManchesterUK

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