Y-box binding protein-1 (YB-1) contributes to both HER2/ErbB2 expression and lapatinib sensitivity in human gastric cancer cells
Menée in vitro et sur des échantillons prélevés sur 111 patients atteints d'un cancer de l'estomac, cette étude met en évidence le rôle joué par la protéine YB-1 dans la régulation de l'expression de HER2 et la réponse au lapatinib
Gene amplification of HER2/ErbB2 occurs in gastric cancer, and the therapeutic efficacy of the HER2-targeted antibody, trastuzumab, has recently been improved against HER2-positive advanced stomach cancer. Here we examined whether Y-box-binding protein-1 (YB-1) could selectively control HER2 gene expression and cellular sensitivity to epidermal growth factor receptor (EGFR) family protein-targeted drugs in human gastric cancer cells. HER2 expression was specifically downregulated by YB-1 silencing using its cognate siRNA, whereas there was less change in the expression of EGFR and HER3. A chromatin immunoprecipitation assay revealed the specific binding of YB-1 to its consensus sequence on the 5-regulatory region of HER2. YB-1 knockdown induced drug resistance to lapatinib, a dual EGFR and HER2 kinase inhibitor, and also to erlotinib, an EGFR kinase inhibitor. Moreover, phosphorylation of protein kinase B (Akt) was not markedly affected by lapatinib or erlotinib when YB-1 was silenced. Nuclear YB-1 expression was significantly (p=0.026) associated with HER2 expression, but not with EGFR or HER3, in patients with gastric cancer (n=111). The YB-1-HER2 axis might therefore be useful for the further development of personalized therapeutics against gastric cancer by HER2-targeted drugs.
http://mct.aacrjournals.org/content/early/2013/02/27/1535-7163.MCT-12-1125.abstract