Protein Kinase Cδ is required for ErbB2-driven mammary gland tumorigenesis and negatively correlates with prognosis in human breast cancer

摘要: Protein kinase C δ (PKCδ) regulates apoptosis in the mammary gland, however, functional contribution of PKCδ to development or progression breast cancer has yet be determined. Meta-analysis ErbB2-positive cancers shows increased expression, and a negative correlation between expression prognosis. Here, we present in-vivo evidence that is essential for gland tumors ErbB2-overexpressing transgenic mouse model, in-vitro required proliferative signaling downstream ErbB2 receptor. Mouse tumor virus (MMTV)-ErbB2 mice lacking (δKO) have latency compared with MMTV-ErbB2 wild-type (δWT) mice, show dramatic decrease Ki-67 staining. To explore relationship ErbB2-driven proliferation more directly, used MCF-10A cells engineered express synthetic ligand-inducible form Depletion short hairpin RNA inhibited ligand-induced growth both two-dimensional (2D) (plastic) three-dimensional (3D) (Matrigel) culture, correlated decreased phosphorylation receptor reduced activation Src MAPK/ERK pathways. Similarly, human cell lines which overexpressed, depletion suppresses proliferation, ERK activation. appears drive through formation an active ErbB2/PKCδ/Src complex, as disrupts association Taken together, our studies first critical regulator ErbB2-mediated tumorigenesis, suggest further investigation target cancer.