Constitutive HER2 signaling promotes breast cancer metastasis through cellular senescence.

Senescence, a terminal cellproliferationarrest, canbe triggered by oncogenes. Oncogene-induced senescence is classically considered a tumor defense barrier. However, several findings show that, under certain circumstances, senescent cells may favor tumor progression because of their secretory phenotype. Here, we show that the expressionindifferentbreastepithelialcelllinesofp95HER2,aconstitutivelyactivefragmentofthetyrosinekinase receptor HER2, results in either increased proliferation or senescence. In senescent cells, p95HER2 elicits a secretome enriched in proteases, cytokines, and growth factors. This secretory phenotype is not a mere consequence of the senescence status and requires continuous HER2 signaling to be maintained. Underscoring thefunctionalrelevanceofthep95HER2-inducedsenescencesecretome,weshowthatp95HER2-inducedsenescent cells promote metastasis in vivo in a non–cell-autonomous manner. Cancer Res; 73(1); 450–8. � 2012 AACR.