Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma

Abstract

We report that human secretory breast carcinoma (SBC), a rare subtype of infiltrating ductal carcinoma, expresses the ETV6-NTRK3 gene fusion previously cloned in pediatric mesenchymal cancers. This gene fusion encodes a chimeric tyrosine kinase with potent transforming activity in fibroblasts. ETV6-NTRK3 expression was confirmed in 12 (92%) of 13 SBC cases, but not in other ductal carcinomas. Retroviral transfer of ETV6-NTRK3 (EN) into murine mammary epithelial cells resulted in transformed cells that readily formed tumors in nude mice. Phenotypically, tumors produced glands and expressed epithelial antigens, confirming that EN transformation is compatible with epithelial differentiation. This represents a recurrent chromosomal rearrangement and expression of a dominantly acting oncogene as a primary event in human breast carcinoma.

Cytogenetic and immunohistochemical characterization of mammary analogue secretory carcinoma of salivary glands

“…The ETV6-NTRK3 gene fusion has been shown in other tumours including congenital mesoblastic nephroma, congenital fibrosarcoma and acute myeloid leukaemia [18]. This translocation facilitates fusion of the transcriptional regulator (ETV6) with membrane receptor kinase (NTRK3) leading to activation of the Ras-MAP kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K)-AKT pathways, subsequently promoting survival and proliferation of neoplastic cells.…”

Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer

“…The second most common class, tyrosine kinases, is also equally involved (5-7%) in the hematological disorders, mesenchymal tumors and epithelial tumors. In addition, several genes, such as ETV6, EWSR1 and HMGA2 ( Table 2), are rearranged in all three subgroups, and one particular fusion gene, ETV6-NTRK3, has been described in entities as diverse as acute myeloid leukemia (AML), infantile fibrosarcoma, mesoblastic nephroma and breast carcinoma [9][10][11][12] . These data strengthen the conclusion from the quantitative comparisons presented above that there are no fundamental tissuespecific differences.…”

Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like carcinoma spectrum

“…Tognon et al 5 recently showed that secretory breast carcinomas are associated with a characteristic balanced translocation, t (12;15), that creates a ETV6-NTRK3 gene fusion. The fusion between ETV6 (TEL) transcription factor and the NTRK3-neurotrophin-3 tyrosine kinase protein occurs in various cell types and lineages.…”

“…The fusion between ETV6 (TEL) transcription factor and the NTRK3-neurotrophin-3 tyrosine kinase protein occurs in various cell types and lineages. 5 This specific translocation was first cloned in pediatric mesenchymal cancers: congenital fibrosarcoma and congenital cellular mesoblastic nephroma, two morphologically similar pediatric mesenchymal tumors with no epithelial features. 6,7 The biological consequence of this translocation is the expression of a chimeric tyrosine kinase protein with a potent transforming activity in very different cell lineages including fibroblasts, and breast epithelial cells.…”