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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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, fewstudies 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 tumorxenograft 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.

Original languageEnglish (US)
Pages (from-to)913-922
Number of pages10
JournalBreast Cancer Research and Treatment
Volume135
Issue number3
DOIs
StatePublished - Oct 1 2012
Externally publishedYes

Fingerprint

Neoplasm Genes
Heterografts
Breast Neoplasms
Gene Expression
Neoplasms
Cluster Analysis
Genes

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Petrillo, L. A., Wolf, D. M., Kapoun, A. M., Wang, N. J., Barczak, A., Xiao, Y., ... Esserman, L. J. (2012). Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors. Breast Cancer Research and Treatment, 135(3), 913-922. https://doi.org/10.1007/s10549-012-2226-y

Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors. / Petrillo, Laura A.; Wolf, Denise M.; Kapoun, Ann M.; Wang, Nicholas J.; Barczak, Andrea; Xiao, Yuanyuan; Korkaya, Hasan; Baehner, Frederick; Lewicki, John; Wicha, Max; Park, John W.; Spellman, Paul T.; Gray, Joe W.; Van'T Veer, Laura; Esserman, Laura J.

In: Breast Cancer Research and Treatment, Vol. 135, No. 3, 01.10.2012, p. 913-922.

Research output: Contribution to journalArticle

Petrillo, LA, Wolf, DM, Kapoun, AM, Wang, NJ, Barczak, A, Xiao, Y, Korkaya, H, Baehner, F, Lewicki, J, Wicha, M, Park, JW, Spellman, PT, Gray, JW, Van'T Veer, L & Esserman, LJ 2012, 'Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors', Breast Cancer Research and Treatment, vol. 135, no. 3, pp. 913-922. https://doi.org/10.1007/s10549-012-2226-y
Petrillo, Laura A. ; Wolf, Denise M. ; Kapoun, Ann M. ; Wang, Nicholas J. ; Barczak, Andrea ; Xiao, Yuanyuan ; Korkaya, Hasan ; Baehner, Frederick ; Lewicki, John ; Wicha, Max ; Park, John W. ; Spellman, Paul T. ; Gray, Joe W. ; Van'T Veer, Laura ; Esserman, Laura J. / Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors. In: Breast Cancer Research and Treatment. 2012 ; Vol. 135, No. 3. pp. 913-922.
@article{b991a0bae210486e96a8c938cf3744d6,
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, fewstudies 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 tumorxenograft 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 = "ALDH1, Breast cancer, CDK5/6, Intrinsic subtype, Mouse model, PAM50, Receptor subtype, Xenograft",
author = "Petrillo, {Laura A.} and Wolf, {Denise M.} and Kapoun, {Ann M.} and Wang, {Nicholas J.} and Andrea Barczak and Yuanyuan Xiao and Hasan Korkaya and Frederick Baehner and John Lewicki and Max Wicha and Park, {John W.} and Spellman, {Paul T.} and Gray, {Joe W.} and {Van'T Veer}, Laura and Esserman, {Laura J.}",
year = "2012",
month = "10",
day = "1",
doi = "10.1007/s10549-012-2226-y",
language = "English (US)",
volume = "135",
pages = "913--922",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",
number = "3",

}

TY - JOUR

T1 - Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors

AU - Petrillo, Laura A.

AU - Wolf, Denise M.

AU - Kapoun, Ann M.

AU - Wang, Nicholas J.

AU - Barczak, Andrea

AU - Xiao, Yuanyuan

AU - Korkaya, Hasan

AU - Baehner, Frederick

AU - Lewicki, John

AU - Wicha, Max

AU - Park, John W.

AU - Spellman, Paul T.

AU - Gray, Joe W.

AU - Van'T Veer, Laura

AU - Esserman, Laura J.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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, fewstudies 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 tumorxenograft 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.

AB - 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, fewstudies 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 tumorxenograft 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.

KW - ALDH1

KW - Breast cancer

KW - CDK5/6

KW - Intrinsic subtype

KW - Mouse model

KW - PAM50

KW - Receptor subtype

KW - Xenograft

UR - http://www.scopus.com/inward/record.url?scp=84866536411&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866536411&partnerID=8YFLogxK

U2 - 10.1007/s10549-012-2226-y

DO - 10.1007/s10549-012-2226-y

M3 - Article

VL - 135

SP - 913

EP - 922

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 3

ER -