Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling

J. Graeme Hodgson, Tiffany Malek, Sophia Bornstein, Sujatmi Hariono, David G. Ginzinger, William J. Muller, Joe Gray

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Receptor tyrosine kinase (RTK) signaling plays a key role in the development of breast cancer. Defining the genes and pathways in the RTK signaling network that are important regulators of tumorigenesis in vivo will unveil potential candidates for targeted therapeutics. To this end, we used microarray comparative genomic hybridization to identify and compare copy number aberrations in five mouse models of breast cancer induced by wild-type and mutated forms of oncogenic ErbB2 or the polyomavirus middle T antigen (PyMT). We observed distinct genomic alterations among the various models, including recurrent chromosome 11 amplifications and chromosome 4 deletions, syntenic with human 17q21-25 and 1p35-36, respectively. Expression of oncogenic Erbb2 (NeuNT) under control of the endogenous Erbb2 promoter results in frequent (85%) amplification at the Erbb2 locus with striking structural similarity to the human amplicon, resulting in overexpression of at least two of the genes, Erbb2 and Grb7. Chromosome 11 amplicons distal to Erbb2 arise in a model (DB) overexpressing a mutant variant of PyMT (Y315/322F) unable to activate phosphatidylinositol 3-kinase. These amplicons are not observed in DB hyperplasias or in tumors overexpressing wild-type PyMT and result in overexpression of Grb2 and Itgb4. Distal chromosome 4 deletions occur in a significantly higher proportion of Erbb2 than PyMT tumors and encompass 14-3-3σ (Stratifin), which is expressed at low or undetectable levels in the majority of NeuNT tumors. Our studies highlight loci and genes important in the regulation of tumorigenic RTK signaling in mammary epithelial cells in vivo.

Original languageEnglish (US)
Pages (from-to)9695-9704
Number of pages10
JournalCancer Research
Volume65
Issue number21
DOIs
StatePublished - Nov 1 2005

Fingerprint

Polyomavirus Transforming Antigens
Receptor Protein-Tyrosine Kinases
Breast Neoplasms
Chromosome Deletion
Chromosomes, Human, Pair 11
Chromosomes, Human, Pair 4
Genes
Phosphatidylinositol 3-Kinase
erbB-2 Genes
Neoplasms
Comparative Genomic Hybridization
Hyperplasia
Carcinogenesis
Breast
Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling. / Hodgson, J. Graeme; Malek, Tiffany; Bornstein, Sophia; Hariono, Sujatmi; Ginzinger, David G.; Muller, William J.; Gray, Joe.

In: Cancer Research, Vol. 65, No. 21, 01.11.2005, p. 9695-9704.

Research output: Contribution to journalArticle

Hodgson, J. Graeme ; Malek, Tiffany ; Bornstein, Sophia ; Hariono, Sujatmi ; Ginzinger, David G. ; Muller, William J. ; Gray, Joe. / Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling. In: Cancer Research. 2005 ; Vol. 65, No. 21. pp. 9695-9704.
@article{6601eefac74d44539354fe8ef6978b65,
title = "Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling",
abstract = "Receptor tyrosine kinase (RTK) signaling plays a key role in the development of breast cancer. Defining the genes and pathways in the RTK signaling network that are important regulators of tumorigenesis in vivo will unveil potential candidates for targeted therapeutics. To this end, we used microarray comparative genomic hybridization to identify and compare copy number aberrations in five mouse models of breast cancer induced by wild-type and mutated forms of oncogenic ErbB2 or the polyomavirus middle T antigen (PyMT). We observed distinct genomic alterations among the various models, including recurrent chromosome 11 amplifications and chromosome 4 deletions, syntenic with human 17q21-25 and 1p35-36, respectively. Expression of oncogenic Erbb2 (NeuNT) under control of the endogenous Erbb2 promoter results in frequent (85{\%}) amplification at the Erbb2 locus with striking structural similarity to the human amplicon, resulting in overexpression of at least two of the genes, Erbb2 and Grb7. Chromosome 11 amplicons distal to Erbb2 arise in a model (DB) overexpressing a mutant variant of PyMT (Y315/322F) unable to activate phosphatidylinositol 3-kinase. These amplicons are not observed in DB hyperplasias or in tumors overexpressing wild-type PyMT and result in overexpression of Grb2 and Itgb4. Distal chromosome 4 deletions occur in a significantly higher proportion of Erbb2 than PyMT tumors and encompass 14-3-3σ (Stratifin), which is expressed at low or undetectable levels in the majority of NeuNT tumors. Our studies highlight loci and genes important in the regulation of tumorigenic RTK signaling in mammary epithelial cells in vivo.",
author = "Hodgson, {J. Graeme} and Tiffany Malek and Sophia Bornstein and Sujatmi Hariono and Ginzinger, {David G.} and Muller, {William J.} and Joe Gray",
year = "2005",
month = "11",
day = "1",
doi = "10.1158/0008-5472.CAN-05-0755",
language = "English (US)",
volume = "65",
pages = "9695--9704",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "21",

}

TY - JOUR

T1 - Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling

AU - Hodgson, J. Graeme

AU - Malek, Tiffany

AU - Bornstein, Sophia

AU - Hariono, Sujatmi

AU - Ginzinger, David G.

AU - Muller, William J.

AU - Gray, Joe

PY - 2005/11/1

Y1 - 2005/11/1

N2 - Receptor tyrosine kinase (RTK) signaling plays a key role in the development of breast cancer. Defining the genes and pathways in the RTK signaling network that are important regulators of tumorigenesis in vivo will unveil potential candidates for targeted therapeutics. To this end, we used microarray comparative genomic hybridization to identify and compare copy number aberrations in five mouse models of breast cancer induced by wild-type and mutated forms of oncogenic ErbB2 or the polyomavirus middle T antigen (PyMT). We observed distinct genomic alterations among the various models, including recurrent chromosome 11 amplifications and chromosome 4 deletions, syntenic with human 17q21-25 and 1p35-36, respectively. Expression of oncogenic Erbb2 (NeuNT) under control of the endogenous Erbb2 promoter results in frequent (85%) amplification at the Erbb2 locus with striking structural similarity to the human amplicon, resulting in overexpression of at least two of the genes, Erbb2 and Grb7. Chromosome 11 amplicons distal to Erbb2 arise in a model (DB) overexpressing a mutant variant of PyMT (Y315/322F) unable to activate phosphatidylinositol 3-kinase. These amplicons are not observed in DB hyperplasias or in tumors overexpressing wild-type PyMT and result in overexpression of Grb2 and Itgb4. Distal chromosome 4 deletions occur in a significantly higher proportion of Erbb2 than PyMT tumors and encompass 14-3-3σ (Stratifin), which is expressed at low or undetectable levels in the majority of NeuNT tumors. Our studies highlight loci and genes important in the regulation of tumorigenic RTK signaling in mammary epithelial cells in vivo.

AB - Receptor tyrosine kinase (RTK) signaling plays a key role in the development of breast cancer. Defining the genes and pathways in the RTK signaling network that are important regulators of tumorigenesis in vivo will unveil potential candidates for targeted therapeutics. To this end, we used microarray comparative genomic hybridization to identify and compare copy number aberrations in five mouse models of breast cancer induced by wild-type and mutated forms of oncogenic ErbB2 or the polyomavirus middle T antigen (PyMT). We observed distinct genomic alterations among the various models, including recurrent chromosome 11 amplifications and chromosome 4 deletions, syntenic with human 17q21-25 and 1p35-36, respectively. Expression of oncogenic Erbb2 (NeuNT) under control of the endogenous Erbb2 promoter results in frequent (85%) amplification at the Erbb2 locus with striking structural similarity to the human amplicon, resulting in overexpression of at least two of the genes, Erbb2 and Grb7. Chromosome 11 amplicons distal to Erbb2 arise in a model (DB) overexpressing a mutant variant of PyMT (Y315/322F) unable to activate phosphatidylinositol 3-kinase. These amplicons are not observed in DB hyperplasias or in tumors overexpressing wild-type PyMT and result in overexpression of Grb2 and Itgb4. Distal chromosome 4 deletions occur in a significantly higher proportion of Erbb2 than PyMT tumors and encompass 14-3-3σ (Stratifin), which is expressed at low or undetectable levels in the majority of NeuNT tumors. Our studies highlight loci and genes important in the regulation of tumorigenic RTK signaling in mammary epithelial cells in vivo.

UR - http://www.scopus.com/inward/record.url?scp=27544442628&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27544442628&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-05-0755

DO - 10.1158/0008-5472.CAN-05-0755

M3 - Article

C2 - 16266989

AN - SCOPUS:27544442628

VL - 65

SP - 9695

EP - 9704

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 21

ER -