title: Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors.
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.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94115, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Petrillo
authors.affiliation: Department Laboratory Medicine, University of California, San Francisco, CA 94115, USA.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Wolf
authors.affiliation: OncoMed Pharmaceuticals, Inc., Redwood City, CA, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.affiliation: Oregon Health & Science University, Portland, OR, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wang
authors.affiliation: Functional Genomics Core, University of California, San Francisco, CA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Barczak
authors.affiliation: Functional Genomics Core, University of California, San Francisco, CA, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Korkaya
authors.affiliation: Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Baehner
authors.affiliation: OncoMed Pharmaceuticals, Inc., Redwood City, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lewicki
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Wicha
authors.affiliation: Department Laboratory Medicine, University of California, San Francisco, CA 94115, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Oregon Health & Science University, Portland, OR, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.affiliation: Oregon Health & Science University, Portland, OR, USA.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.affiliation: Department Laboratory Medicine, University of California, San Francisco, CA 94115, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Van't Veer
authors.affiliation: Department of Surgery, University of California, San Francisco, CA, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Esserman
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D005810:Multigene Family; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000080924:Aldehyde Dehydrogenase 1 Family; D014408:Biomarkers, Tumor; D007527:Isoenzymes; D018719:Erb-b2 Receptor Tyrosine Kinases; D050697:Retinal Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; C508053:ERBB2 protein, human