Skip to main content

Advertisement

SpringerLink
Log in

Radiation Resistance of Breast Cancer Stem Cells: Understanding the Clinical Framework

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Meta-analyses of tens of thousands of women treated with radiation as a component of their breast cancer treatment have shown that radiation improves overall survival from breast cancer in women with early stage and advanced disease. However, data suggest that breast cancer stem/progenitor cells can be enriched after radiation and that breast cancer stem/progenitor clonogens are particularly resistant to radiation. Potentially resistant breast cancer stem/progenitor populations appear to be over-represented in estrogen receptor negative breast cancer and indeed, clinically these cancers are more resistant to radiation than estrogen receptor positive breast cancers. Emerging pre-clinical data suggest that targeting cancer stem/progenitor survival pathways may lead to effective radiosensitization in subgroups of patients with resistant disease. Herein, preclinical studies are reviewed in the context of the clinical framework.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2

Similar content being viewed by others

Abbreviations

IR:

Ionizing radiation

Sca1:

stem cell antigen 1

ATM:

ataxiatelangiectasia-mutated

EGF:

epidermal growth factor

bFGF:

basic fibroblast growth factor

DNA:

deoxyribonucleic acid

ROS:

reactive oxygen species

MECs:

mammary epithelial cells

ER:

estrogen receptor

HSCs:

hematopoetic stem cells

TICs:

tumor-initiating cells

References

  1. Carlson RW, McCormick B. Update: NCCN breast cancer clinical practice guidelines. J Natl Compr Canc Netw 2005;3(Suppl 1):S7–11.

    PubMed  Google Scholar 

  2. Recht A, Edge SB, Solin LJ, Robinson DS, Estabrook A, Fine RE, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19(5):1539–69.

    PubMed  CAS  Google Scholar 

  3. van der Linden YM, Dijkstra SP, Vonk EJ, Marijnen CA, Leer JW. Prediction of survival in patients with metastases in the spinal column: results based on a randomized trial of radiotherapy. Cancer 2005;103(2):320–8. doi:10.1002/cncr.20756.

    Article  PubMed  Google Scholar 

  4. Rades D, Veninga T, Stalpers LJ, Schulte R, Hoskin PJ, Poortmans P, et al. Prognostic factors predicting functional outcomes, recurrence-free survival, and overall survival after radiotherapy for metastatic spinal cord compression in breast cancer patients. Int J Radiat Oncol Biol Phys 2006;64(1):182–8. doi:10.1016/j.ijrobp.2005.06.036.

    PubMed  Google Scholar 

  5. Wadasadawala T, Gupta S, Bagul V, Patil N. Brain metastases from breast cancer: management approach. J Cancer Res Ther 2007;3(3):157–65.

    Article  PubMed  Google Scholar 

  6. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E. 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 2005;366(9503):2087–106.

    PubMed  CAS  Google Scholar 

  7. Gebski V, Lagleva M, Keech A, Simes J, Langlands AO. Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: a clinical perspective. J Natl Cancer Inst 2006;98(1):26–38.

    PubMed  Google Scholar 

  8. 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(5):515–20.

    PubMed  CAS  Google Scholar 

  9. Smith GH, Medina D. A morphologically distinct candidate for an epithelial stem cell in mouse mammary gland. J Cell Sci 1988;90(Pt 1):173–83.

    PubMed  Google Scholar 

  10. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98(19):10869–74. doi:10.1073/pnas.191367098.

    Article  PubMed  CAS  Google Scholar 

  11. Shin BK, Lee Y, Lee JB, Kim HK, Lee JB, Cho SJ, et al. Breast carcinomas expressing basal markers have poor clinical outcome regardless of estrogen receptor status. Oncol Rep 2008;19(3):617–25.

    PubMed  Google Scholar 

  12. Woodward WA, Strom EA, Tucker SL, Katz A, McNeese MD, Perkins GH, et al. Locoregional recurrence after doxorubicin-based chemotherapy and postmastectomy: implications for breast cancer patients with early-stage disease and predictors for recurrence after postmastectomy radiation. Int J Radiat Oncol Biol Phys 2003;57(2):336–44. doi:10.1016/S0360-3016(03)00593-5.

    Article  PubMed  CAS  Google Scholar 

  13. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 2008;26(14):2373–8. doi:10.1200/JCO.2007.14.4287.

    Article  PubMed  Google Scholar 

  14. Kyndi M, Sorensen FB, Knudsen H, Overgaard M, Nielsen HM, Overgaard J. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol 2008;26(9):1419–26. doi:10.1200/JCO.2007.14.5565.

    Article  PubMed  CAS  Google Scholar 

  15. Regan J, Smalley M. Prospective isolation and functional analysis of stem and differentiated cells from the mouse mammary gland. Stem Cell Rev 2007;3(2):124–36. doi:10.1007/s12015-007-0017-3.

    Article  PubMed  CAS  Google Scholar 

  16. Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 2008;8(7):545–54. doi:10.1038/nrc2419.

    Article  PubMed  CAS  Google Scholar 

  17. Brown JM, Wouters BG. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 1999;59(7):1391–9.

    PubMed  CAS  Google Scholar 

  18. Hill RP, Milas L. The proportion of stem cells in murine tumors. Int J Radiat Oncol Biol Phys 1989;16(2):513–8.

    PubMed  CAS  Google Scholar 

  19. Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, et al. Purification and unique properties of mammary epithelial stem cells. Nature 2006;439(7079):993–7.

    PubMed  CAS  Google Scholar 

  20. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006;439(7072):84–8. doi:10.1038/nature04372.

    Article  PubMed  CAS  Google Scholar 

  21. Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrell F, Edwards D, et al. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res 2008;68(12):4674–82. doi:10.1158/0008-5472.CAN-07-6353.

    Article  PubMed  CAS  Google Scholar 

  22. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100(7):3983–8. doi:10.1073/pnas.0530291100.

    Article  PubMed  CAS  Google Scholar 

  23. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007;1(5):555–67. doi:10.1016/j.stem.2007.08.014.

    Article  PubMed  CAS  Google Scholar 

  24. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003;17(10):1253–70. doi:10.1101/gad.1061803.

    Article  PubMed  CAS  Google Scholar 

  25. Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 2008;10(2):R25. doi:10.1186/bcr1982.

    Article  PubMed  CAS  Google Scholar 

  26. Phillips TM, McBride WH, Pajonk F. The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 2006;98(24):1777–85.

    Article  PubMed  Google Scholar 

  27. Munshi A, Hobbs M, Meyn RE. Clonogenic cell survival assay. Methods Mol Med 2005;110:21–8.

    PubMed  Google Scholar 

  28. Wollman R, Yahalom J, Maxy R, Pinto J, Fuks Z. Effect of epidermal growth factor on the growth and radiation sensitivity of human breast cancer cells in vitro. Int J Radiat Oncol Biol Phys 1994;30(1):91–8.

    PubMed  CAS  Google Scholar 

  29. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996;183(4):1797–806. doi:10.1084/jem.183.4.1797.

    Article  PubMed  CAS  Google Scholar 

  30. 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(1):42–56. doi:10.1006/dbio.2002.0625.

    Article  PubMed  CAS  Google Scholar 

  31. Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM. WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci U S A 2007;104(2):618–23. doi:10.1073/pnas.0606599104.

    Article  PubMed  CAS  Google Scholar 

  32. Chen MS, Woodward WA, Behbod F, Peddibhotla S, Alfaro MP, Buchholz TA. Wnt/beta-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line. J Cell Sci 2007;120(Pt 3):468–77. doi:10.1242/jcs.03348.

    Article  PubMed  CAS  Google Scholar 

  33. Potten CS. Radiation, the ideal cytotoxic agent for studying the cell biology of tissues such as the small intestine. Radiat Res 2004;161(2):123–36. doi:10.1667/RR3104.

    Article  PubMed  CAS  Google Scholar 

  34. Hall EJ. Radiobiology for the radiologist. 5th ed. Philadelphia: Lippincott, Wiliams & Wilkins; 2000.

    Google Scholar 

  35. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444(7120):756–60. doi:10.1038/nature05236.

    Article  PubMed  CAS  Google Scholar 

  36. Xiao Y, Ye Y, Yearsley K, Jones S, Barsky SH. The lymphovascular embolus of inflammatory breast cancer expresses a stem cell-like phenotype. Am J Pathol 2008;173(2):561–74. doi:10.2353/ajpath.2008.071214.

    Article  PubMed  CAS  Google Scholar 

  37. Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 2007;110(8):3056–63. doi:10.1182/blood-2007-05-087759.

    Article  PubMed  CAS  Google Scholar 

  38. Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Liu Y, et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 2008;205(10):2397–408. doi:10.1084/jem.20081297.

    Article  PubMed  CAS  Google Scholar 

  39. Ihemelandu CU, Leffall LD Jr, Dewitty RL, Naab TJ, Mezghebe HM, Makambi KH, et al. Molecular breast cancer subtypes in premenopausal and postmenopausal African–American women: age-specific prevalence and survival. J Surg Res 2007;143(1):109–18. doi:10.1016/j.jss.2007.03.085.

    Article  PubMed  CAS  Google Scholar 

  40. Ihemelandu CU, Naab TJ, Mezghebe HM, Makambi KH, Siram SM, Leffall LD Jr, et al. Basal cell-like (triple-negative) breast cancer, a predictor of distant metastasis in African American women. Am J Surg 2008;195(2):153–8. doi:10.1016/j.amjsurg.2007.09.033.

    Article  PubMed  Google Scholar 

  41. Anonymous. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2000;355(9217):1757–70. doi:10.1016/S0140-6736(00)02263-7.

Download references

Acknowledgements

The authors would like to acknowledge the Morgan Welch Inflammatory Breast Cancer Research Program and Clinic; The State of Texas Grant for Rare and Aggressive Cancers; The American Airlines Komen Foundation Promise Grant KGO81287; The University of Texas Institutional Research Grant, K12-5611B through the University of Texas Health Sciences Center from the National Institute of Health; R01CA138239-01; IRG The University of Texas M.D. Anderson Cancer Center.

Author information

Authors and Affiliations

  1. Division of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Bisrat G. Debeb & Wei Xu

  2. Division of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, P.O. Box 1202, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Wendy A. Woodward

Authors
  1. Bisrat G. Debeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wendy A. Woodward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wendy A. Woodward.

Additional information

Bisrat G. Debeb and Wei Xu contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Debeb, B.G., Xu, W. & Woodward, W.A. Radiation Resistance of Breast Cancer Stem Cells: Understanding the Clinical Framework. J Mammary Gland Biol Neoplasia 14, 11–17 (2009). https://doi.org/10.1007/s10911-009-9114-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-009-9114-z

Keywords

Search

Navigation