SPSB1 Promotes Breast Cancer Recurrence by Potentiating c-MET Signaling
Menée à l'aide de modèles murins génétiquement modifiés, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation c-MET, la protéine SPSB1 favorise la récidive d'un cancer du sein
Breast cancer mortality is principally due to tumor recurrence, however the molecular mechanisms underlying this process are poorly understood. We now demonstrate that the SOCS protein SPSB1 is spontaneously up-regulated during mammary tumor recurrence and is both necessary and sufficient to promote tumor recurrence in genetically engineered mouse models. The recurrence-promoting effects of SPSB1 result from its ability to protect cells from apoptosis induced by HER2/neu pathway inhibition or chemotherapy. This, in turn, is attributable to SPSB1 potentiation of c-MET signaling, such that pre-existing SPSB1-overexpressing tumor cells are selected for following HER2/neu down-regulation. Consistent with this, SPSB1 expression is positively correlated with c-MET activity in human breast cancers and with an increased risk of relapse in breast cancer patients in a manner that is dependent upon c-MET-activity. Our findings define a novel pathway that contributes to breast cancer recurrence and provide the first evidence implicating SPSB proteins in cancer.
Cancer Discovery 2014