Resource | Published:

Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes

Nature Medicine volume 17, pages 15141520 (2011) | Download Citation

Abstract

Development and preclinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts illustrate the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for women with newly diagnosed breast cancer; orthotopic breast tumor grafting is a step toward individualized models for tumor growth, metastasis and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Anticancer drug development: the grand challenges. Nat. Rev. Drug Discov. 9, 253–254 (2010).

  2. 2.

    Human breast cancer cell lines as models of growth regulation and disease progression. J. Mammary Gland Biol. Neoplasia 1, 111–121 (1996).

  3. 3.

    , & Modeling metastasis in the mouse. Curr. Opin. Pharmacol. 10, 571–577 (2010).

  4. 4.

    , , , & Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat. Rev. Cancer 11, 135–141 (2011).

  5. 5.

    et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10, 515–527 (2006).

  6. 6.

    et al. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS ONE 4, e6146 (2009).

  7. 7.

    The role of preclinical animal models in breast cancer drug development. Breast Cancer Res. 11 (suppl. 3), S22 (2009).

  8. 8.

    , & Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin. Cancer Res. 9, 4227–4239 (2003).

  9. 9.

    et al. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc. Natl. Acad. Sci. USA 107, 18115–18120 (2010).

  10. 10.

    A self-renewal assay for cancer stem cells. Cancer Chemother. Pharmacol. 56 (suppl. 1), 64–68 (2005).

  11. 11.

    et al. Xenografts of primary human gynecological tumors grown under the renal capsule of NOD/SCID mice show genetic stability during serial transplantation and respond to cytotoxic chemotherapy. Gynecol. Oncol. 110, 256–264 (2008).

  12. 12.

    et al. Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice. Nat. Protoc. 4, 1670–1680 (2009).

  13. 13.

    et al. A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res. 69, 3364–3373 (2009).

  14. 14.

    et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010).

  15. 15.

    , , , & Triple-negative breast cancer: disease entity or title of convenience? Nat. Rev. Clin. Oncol. 7, 683–692 (2010).

  16. 16.

    et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).

  17. 17.

    et al. Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rγ null mice generate a faster and more efficient disease compared to other NOD/scid-related strains. Int. J. Cancer 123, 2222–2227 (2008).

  18. 18.

    et al. NOD/SCID/γ(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100, 3175–3182 (2002).

  19. 19.

    Models of breast cancer: quo vadis, animal modeling? Breast Cancer Res. 6, 31–38 (2004).

  20. 20.

    & Mesenchymal stem cells in the pathogenesis and therapy of breast cancer. J. Mammary Gland Biol. Neoplasia 15, 399–409 (2010).

  21. 21.

    et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

  22. 22.

    et al. A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin. Cancer Res. 13, 3989–3998 (2007).

  23. 23.

    et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).

  24. 24.

    et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med. 351, 2817–2826 (2004).

  25. 25.

    et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160–1167 (2009).

  26. 26.

    et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

  27. 27.

    et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 98, 10869–10874 (2001).

  28. 28.

    et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl. Acad. Sci. USA 100, 8418–8423 (2003).

  29. 29.

    et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7, 96 (2006).

  30. 30.

    , , , & Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells 29, 11–19 (2011).

  31. 31.

    et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proc. Natl. Acad. Sci. USA 101, 4966–4971 (2004).

  32. 32.

    & Targeting breast cancer stem cells. J. Clin. Oncol. 28, 4006–4012 (2010).

  33. 33.

    , , & Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res. 17, 3–14 (2007).

  34. 34.

    Green fluorescent protein to visualize cancer progression and metastasis. Methods Enzymol. 302, 20–31 (1999).

  35. 35.

    , , , & Lentiviral transduction of mammary stem cells for analysis of gene function during development and cancer. Cell Stem Cell 2, 90–102 (2008).

Download references

Acknowledgements

We are grateful to the individuals who donated tissue toward this endeavor and the Associated Regional and University Pathologists Research Institute staff for performing the clinical stains. This work was supported by funding from the Department of Defense Breast Cancer Research Program (to A.L.W.; BC075015), the American Association for Cancer Research and Breast Cancer Research Foundation (to A.L.W.; 07−60−26−WELM) and the Huntsman Cancer Foundation. We also used the Huntsman Cancer Institute Tissue Resource and Application Core and Comparative Oncology Core facilities, which is supported in part by P30 CA042014 (to the Huntsman Cancer Institute).

Author information

Affiliations

  1. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

    • Yoko S DeRose
    • , Guoying Wang
    • , Yi-Chun Lin
    • , Bryan E Welm
    •  & Alana L Welm
  2. Department of Pathology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

    • Philip S Bernard
    • , Rachel Factor
    •  & Inge J Stijleman
  3. The Associated Regional and University Pathologists Institute for Clinical and Experimental Pathology, Salt Lake City, Utah, USA.

    • Philip S Bernard
    •  & Mark T W Ebbert
  4. Department of Internal Medicine, Medical Oncology Division, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

    • Saundra S Buys
  5. Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

    • Cindy Matsen
    • , Edward Nelson
    • , Leigh Neumayer
    •  & Bryan E Welm
  6. Bioinformatics Core Facility, Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.

    • Brett A Milash
  7. Department of Orthopaedic Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

    • R Lor Randall

Authors

  1. Search for Yoko S DeRose in:

  2. Search for Guoying Wang in:

  3. Search for Yi-Chun Lin in:

  4. Search for Philip S Bernard in:

  5. Search for Saundra S Buys in:

  6. Search for Mark T W Ebbert in:

  7. Search for Rachel Factor in:

  8. Search for Cindy Matsen in:

  9. Search for Brett A Milash in:

  10. Search for Edward Nelson in:

  11. Search for Leigh Neumayer in:

  12. Search for R Lor Randall in:

  13. Search for Inge J Stijleman in:

  14. Search for Bryan E Welm in:

  15. Search for Alana L Welm in:

Contributions

Y.S.D., G.W., Y.-C.L., M.T.W.E., C.M. and I.J.S. performed the experiments. S.S.B., E.N., L.N. and R.L.R. provided tissues. Y.S.D., G.W., P.S.B., R.F., B.A.M., B.E.W. and A.L.W. analyzed the data. A.L.W. wrote the paper, and B.E.W. and P.S.B. edited the paper. A.L.W. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Alana L Welm.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Methods, Supplementary Results and Discussion, Supplementary Tables 2 and 3 and Supplementary Figures 1–32.

Excel files

  1. 1.

    Supplementary Table 1

    Detailed patient, tumor and tumor graft information.

Text files

  1. 1.

    Supplementary Table 4

    Expression data from preclustered intrinsic gene set.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.2454

Further reading