ETV6-NTRK3 Fusion Oncogene Initiates Breast Cancer from Committed Mammary Progenitors via Activation of AP1 Complex

• Published in: Cancer cell Vol. 12; no. 6; pp. 542 - 558
• Main Authors: Li, Zhe, Tognon, Cristina E., Godinho, Frank J., Yasaitis, Laura, Hock, Hanno, Herschkowitz, Jason I., Lannon, Chris L., Cho, Eunah, Kim, Seong-Jin, Bronson, Roderick T., Perou, Charles M., Sorensen, Poul H., Orkin, Stuart H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2007
• Subjects: Alleles; Animals; Breast Neoplasms - genetics; Breast Neoplasms - pathology; CD24 Antigen - metabolism; Cell Transformation, Neoplastic; CELLCYCLE; Epithelial Cells - metabolism; Epithelial Cells - pathology; ETS Translocation Variant 6 Protein; Female; Genes, Dominant; Humans; Integrases - metabolism; Mammary Glands, Animal - pathology; Mammary Neoplasms, Animal - pathology; Mice; Multigene Family; Neoplastic Stem Cells - pathology; Oncogene Proteins, Fusion - metabolism; Parity; Penetrance; Pregnancy; Proto-Oncogene Proteins c-ets - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Repressor Proteins - metabolism; STEMCELL; Transcription Factor AP-1 - metabolism; STEMCELL; CELLCYCLE
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2007.11.012

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 CD61+ luminal progenitors are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given the 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 preclinical models.