ral ssBioMed CentBMC Cell Biology Open AcceResearch article Inhibition of eIF2 dephosphorylation inhibits ErbB2-induced deregulation of mammary acinar morphogenesis

Background: The ErbB2/Her2/Neu receptor tyrosine kinase is amplified in ~30 % of human breast cancers. Phosphorylation of the translation initiation factor, eIF2 inhibits global protein synthesis and activates a stress signaling and growth suppressive program. We have shown that forced phosphorylation of eIF2 can suppress head and neck, colorectal carcinoma and multiple myeloma tumor growth and/or survival. Here we explore whether ErbB2 modulates eIF2 phosphorylation and whether forced phosphorylation of the latter can antagonize ErbB2 deregulation of mammary acinar morphogenesis. Results: We tested whether ErbB2 signaling influenced eIF2 signaling and whether enhanced phosphorylation of the latter affected ErbB2-deregulated mammary acinar development. We obtained stable MCF10A cells overexpressing wild-type (Wt) Neu/ErbB2 or a constitutively active (CA) variant via retroviral delivery or mammary tumor cells from MMTV-Neu tumors. Western blotting, RT-PCR and confocal microscopy were used to analyze the effects of ErbB2 activation on eIF2 signaling and the effect of the GADD34-PP1C inhibitor salubrinal. Wt- and MMTV-Neu cells formed aberrant acini structures resembling DCIS, while CA-ErbB2 overexpression induced invasive lesions. In these structures we foun