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Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors

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Abstract

Though xenografts are used extensively for drug development in breast cancer, how well xenografts reflect the breadth of primary breast tumor subtypes has not been well characterized. Moreover, few studies have compared the gene expression of xenograft tumors to the primary tumors from which they were derived. Here we investigate whether the ability of human breast tumors (n = 20) to create xenografts in immune-deficient mice is associated with breast cancer immunohistochemical (IHC) and intrinsic subtype. We also characterize how precisely the gene expression of xenografts reprises that of parent breast tumors, using hierarchical clustering and other correlation-based techniques applied to Agilent 44K gene expression data from 16 samples including four matched primary tumor-xenograft pairs. Of the breast tumors studied, 25 % (5/20) generated xenografts. Receptor and intrinsic subtype were significant predictors of xenograft success, with all (4/4) triple-negative (TN) tumors and no (0/12) HR+Her2− tumors forming xenografts (P = 0.0005). Tumor cell expression of ALDH1, a stem cell marker, trended toward successful engraftment (P = 0.14), though CDK5/6, a basal marker, did not. Though hierarchical clustering across the 500 most variable genes segregated human breast tumors from xenograft tumors, when clustering was performed over the PAM50 gene set the primary tumor-xenograft pairs clustered together, with all IHC subtypes clustered in distinct groups. Greater similarity between primary tumor-xenograft pairs relative to random pairings was confirmed by calculation of the within-pair between-pair scatter ratio (WPBPSR) distribution (P = 0.0269), though there was a shift in the xenografts toward more aggressive features including higher proliferation scores relative to the primary. Triple-negative breast tumors demonstrate superior ability to create xenografts compared to HR+ tumors, which may reflect higher proliferation or relatively stroma-independent growth of this subtype. Xenograft tumors’ gene expression faithfully resembles that of their parent tumors, yet also demonstrates a shift toward more aggressive molecular features.

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Acknowledgments

The authors would like to thank the patients who participated in the study. We would like to thank Angie Park for her xenograft development work at OncoMed. This work was supported by funding from OncoMed Pharmaceuticals, Inc. the National Cancer Institute Specialized Program of Research Excellence in Breast Cancer, the Doris Duke Charitable Foundation and the NIH/NCRR/OD UCSF-CTSI Grant Number TL1 RR024129. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Conflicts of interest

Ann Kapoun and John Lewicki are employees and stock holders of OncoMed Pharmaceuticals, Inc.

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, CA, 94115, USA

    Laura A. Petrillo

  2. Department of Laboratory Medicine, University of California, San Francisco, CA, 94115, USA

    Denise M. Wolf, John W. Park & Laura van’t Veer

  3. OncoMed Pharmaceuticals, Inc., Redwood City, CA, USA

    Ann M. Kapoun & John Lewicki

  4. Department of Pathology, University of California, San Francisco, CA, USA

    Frederick Baehner

  5. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Hasan Korkaya & Max Wicha

  6. Oregon Health & Science University, Portland, OR, USA

    Nicholas J. Wang, Paul T. Spellman & Joe W. Gray

  7. Functional Genomics Core, University of California, San Francisco, CA, USA

    Andrea Barczak & Yuanyuan Xiao

  8. Department of Surgery, University of California, San Francisco, CA, USA

    Laura J. Esserman

Authors
  1. Laura A. Petrillo
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  2. Denise M. Wolf
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  3. Ann M. Kapoun
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  4. Nicholas J. Wang
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  9. John Lewicki
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  10. Max Wicha
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  13. Joe W. Gray
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  14. Laura van’t Veer
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Corresponding authors

Correspondence to Laura A. Petrillo or Denise M. Wolf.

Additional information

Laura Petrillo and Denise M. Wolf contributed equally to this work.

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Petrillo, L.A., Wolf, D.M., Kapoun, A.M. et al. Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors. Breast Cancer Res Treat 135, 913–922 (2012). https://doi.org/10.1007/s10549-012-2226-y

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  • DOI: https://doi.org/10.1007/s10549-012-2226-y

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