Brief Report

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. PetrilloAffiliated withDepartment of Medicine, University of California Email author 
  • , Denise M. WolfAffiliated withDepartment of Laboratory Medicine, University of California Email author 
  • , Ann M. KapounAffiliated withOncoMed Pharmaceuticals, Inc.
  • , Nicholas J. WangAffiliated withOregon Health & Science University
  • , Andrea BarczakAffiliated withFunctional Genomics Core, University of California
  • , Yuanyuan XiaoAffiliated withFunctional Genomics Core, University of California
  • , Hasan KorkayaAffiliated withDepartment of Internal Medicine, University of Michigan
  • , Frederick BaehnerAffiliated withDepartment of Pathology, University of California
  • , John LewickiAffiliated withOncoMed Pharmaceuticals, Inc.
    • , Max WichaAffiliated withDepartment of Internal Medicine, University of Michigan
    • , John W. ParkAffiliated withDepartment of Laboratory Medicine, University of California
    • , Paul T. SpellmanAffiliated withOregon Health & Science University
    • , Joe W. GrayAffiliated withOregon Health & Science University
    • , Laura van’t VeerAffiliated withDepartment of Laboratory Medicine, University of California
    • , Laura J. EssermanAffiliated withDepartment of Surgery, University of California

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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.

Keywords

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