Molecular characterization of the transition to malignancy in a genetically engineered mouse-based model of ductal carcinoma in situ

Ruria Namba, Jeannie E. Maglione, Lawrence J T Young, Alexander D Borowsky, Robert Cardiff, Carol L. MacLeod, Jeffrey Gregg

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Abstract

A transplantable model of human ductal carcinoma in situ that progresses to invasive carcinoma was developed from a genetically engineered mouse (GEM). Additional lines were established using early mammary premalignant lesions from transgenic MMTV-PyV-mT mice. These lines were verified to be premalignant and transplanted repeatedly to establish stable and predictable properties. Here, we report the first in-depth molecular analysis of neoplastic progression occurring in one premalignant transplantable GEM-derived line. Oligonucleotide microarrays showed that many genes are differentially expressed between the quiescent and prelactating mammary gland and the premalignant GEM outgrowth. In contrast, a small but consistent group of genes was associated with the transformation from premalignancy to tumor. This suggests that the majority of gene expression changes occur during the premalignant transition from normal to premalignancy, whereas many fewer changes occur during the malignant transition from premalignancy to invasive carcinoma. The premalignant transition is associated with several cell cycle-related genes and the up-regulation of oncogenes is associated with various cancers (Ccnd11, Cdk4, Myb, and Ect2). The changes identified in the malignant transition included genes previously associated with human breast cancer progression. Misregulation of the insulin-like growth factor and transforming growth factor-β signaling pathways and the stromal-epithelial interaction were implicated. Our results suggest that this transplantable GEM-based model recapitulates human ductal carcinoma in situ at both histologic and molecular levels. With consistent tumor latency and molecular profiles, this model provides an experimental platform that can be used to assess functional genomics and molecular pharmacology and to test promising chemoprevention strategies.

Original languageEnglish (US)
Pages (from-to)453-463
Number of pages11
JournalMolecular Cancer Research
Volume2
Issue number8
StatePublished - Aug 2004

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Carcinoma, Intraductal, Noninfiltrating
Neoplasms
Genes
Carcinoma
cdc Genes
Molecular Models
Chemoprevention
Transforming Growth Factors
Somatomedins
Human Mammary Glands
Genomics
Oligonucleotide Array Sequence Analysis
Oncogenes
Breast
Up-Regulation
Pharmacology
Breast Neoplasms
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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Molecular characterization of the transition to malignancy in a genetically engineered mouse-based model of ductal carcinoma in situ. / Namba, Ruria; Maglione, Jeannie E.; Young, Lawrence J T; Borowsky, Alexander D; Cardiff, Robert; MacLeod, Carol L.; Gregg, Jeffrey.

In: Molecular Cancer Research, Vol. 2, No. 8, 08.2004, p. 453-463.

Research output: Contribution to journalArticle

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