Transcriptomics

Dataset Information

17

Transcription profiling of mammary tissues from mouse model of breast cancer conditionally expressing Etv6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation


ABSTRACT: For the largest class of human tumors, those of epithelial origin, little is known about their initiating genetic hits or cells of origin. Whether tissue stem cells or more committed progenitors are targets for transformation is also uncertain. Experience in hematopoietic malignancies and sarcomas teaches that recurrent chromosomal translocations represent initiating oncogenic events. To develop a system in which epithelial tumorigenesis can be assessed from the initial event to frank malignancy, we have generated mice that conditionally express the Etv6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of one form of human breast cancer. Activation of EN expression in mammary tissues by Whey acidic protein (Wap) promoter-driven Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that committed, bipotent or CD61+ luminal alveolar progenitors, can be targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through the AP1 complex. Our model supports the existence of an epithelial cell hierarchy in both normal mammary glands and malignancy. To our knowledge, this is the first murine model of human epithelial cancer based on a recurrent chromosomal translocation. Given increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of novel preclinical models. Experiment Overall Design: Reference X Sample

ORGANISM(S): Mus musculus  

SUBMITTER: Charles Perou  

PROVIDER: E-GEOD-9343 | ArrayExpress | 2008-06-16

SECONDARY ACCESSION(S): GSE9343PRJNA103029

REPOSITORIES: GEO, ArrayExpress

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Publications

ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex.

Li Zhe Z   Tognon Cristina E CE   Godinho Frank J FJ   Yasaitis Laura L   Hock Hanno H   Herschkowitz Jason I JI   Lannon Chris L CL   Cho Eunah E   Kim Seong-Jin SJ   Bronson Roderick T RT   Perou Charles M CM   Sorensen Poul H PH   Orkin Stuart H SH  

Cancer cell 20071201 6


To better understand the cellular origin of breast cancer, we developed a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Wap-Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that, in nulliparous Wap-Cre;EN females, committed alveolar bipotent or  ...[more]

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