Breast Cancer Research and Treatment

, Volume 135, Issue 3, pp 913–922

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

  • Laura A. Petrillo
  • Denise M. Wolf
  • Ann M. Kapoun
  • Nicholas J. Wang
  • Andrea Barczak
  • Yuanyuan Xiao
  • Hasan Korkaya
  • Frederick Baehner
  • John Lewicki
  • Max Wicha
  • John W. Park
  • Paul T. Spellman
  • Joe W. Gray
  • Laura van’t Veer
  • Laura J. Esserman
Brief Report

DOI: 10.1007/s10549-012-2226-y

Cite this article as:
Petrillo, L.A., Wolf, D.M., Kapoun, A.M. et al. Breast Cancer Res Treat (2012) 135: 913. doi:10.1007/s10549-012-2226-y

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.

Keywords

Mouse model Breast cancer Xenograft Receptor subtype Intrinsic subtype ALDH1 CDK5/6 PAM50 

Supplementary material

10549_2012_2226_MOESM1_ESM.xls (32 kb)
Supplementary material 1 (XLS 32 kb)

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Laura A. Petrillo
    • 1
  • Denise M. Wolf
    • 2
  • Ann M. Kapoun
    • 3
  • Nicholas J. Wang
    • 6
  • Andrea Barczak
    • 7
  • Yuanyuan Xiao
    • 7
  • Hasan Korkaya
    • 5
  • Frederick Baehner
    • 4
  • John Lewicki
    • 3
  • Max Wicha
    • 5
  • John W. Park
    • 2
  • Paul T. Spellman
    • 6
  • Joe W. Gray
    • 6
  • Laura van’t Veer
    • 2
  • Laura J. Esserman
    • 8
  1. 1.Department of MedicineUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of Laboratory MedicineUniversity of CaliforniaSan FranciscoUSA
  3. 3.OncoMed Pharmaceuticals, Inc.Redwood CityUSA
  4. 4.Department of PathologyUniversity of CaliforniaSan FranciscoUSA
  5. 5.Department of Internal MedicineUniversity of MichiganAnn ArborUSA
  6. 6.Oregon Health & Science UniversityPortlandUSA
  7. 7.Functional Genomics CoreUniversity of CaliforniaSan FranciscoUSA
  8. 8.Department of SurgeryUniversity of CaliforniaSan FranciscoUSA

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