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

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.

The ETV6-NTRK3 chimeric tyrosine kinase suppresses TGF-beta signaling by inactivating the TGF-beta type II receptor.

An emerging theme in cancer biology is that although some malignancies occur through the sequential acquisition of different genetic alterations, certain dominantly acting oncoproteins such as those associated with chromosomal translocations have multiple functions and do not require additional mutations for cell transformation. The ETV6-NTRK3 (EN) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages, functions as a constitutively active protein tyrosine kinase. Here, we show that EN suppresses TGF-beta signaling by directly binding to the type II TGF-beta receptor, thereby preventing it from interacting with the type I TGF-beta receptor.

ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages.

The ETV6-NTRK3 (TEL-TRKC) gene fusion was discovered by breakpoint analysis of the t(12;15)(p13;q25) translocation associated with congenital fibrosarcoma, a pediatric soft tissue malignancy. ETV6-NTRK3 (EN) encodes the sterile alpha motif oligomerization domain of the ETV6 (TEL) transcription factor linked to the protein tyrosine kinase domain of the neurotrophin-3 receptor NTRK3 (TRKC). The EN chimeric oncoprotein links to multiple signaling cascades including Ras-MAP kinase and PI3K-AKT through the IRS-1 adapter protein.

A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation.

Receptor tyrosine kinases are integral components of cellular signaling pathways and are frequently deregulated in malignancies. The NTRK family of neurotrophin receptors mediate neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in oncogenesis. The ETV6-NTRK3 (EN) gene fusion occurs in human pediatric spindle cell sarcomas and secretory breast carcinoma, and encodes the oligomerization domain of the ETV6 transcription factor fused to the protein-tyrosine kinase domain of NTRK3.