Mammary tumor formation and metastasis evoked by a HER2 splice variant

The HER2 gene is amplified and overexpressed in approximately 20% of invasive breast cancers where it is associated with metastasis and poor prognosis. Here, we describe a constitutively active splice variant of HER2 (Delta-HER2) in human mammary epithelial cells that evokes aggressive breast cancer phenotypes. Delta-HER2 overexpression in mammary epithelial cells was sufficient to reduce apoptosis, increase proliferation, and induce expression of mesenchymal markers, features that were associated with greater invasive potential in three-dimensional cultures in vitro and more aggressive tumorigenicity and metastasis in vivo. In contrast, overexpression of wild-type HER2 was insufficient at evoking such effects. Unbiased protein-tyrosine phosphorylation profiling in Delta-HER2-expressing cells revealed increased phosphorylation of several signaling proteins not previously known to be controlled by the HER2 pathway. Furthermore, microarray expression analysis revealed activation of genes known to be highly expressed in ER-negative, high-grade, and metastatic primary breast tumors. Together, our results provide mechanistic insights into the activity of a highly pathogenic splice variant of HER2.