title: Downregulation of Erbin in Her2-overexpressing breast cancer cells promotes cell migration and induces trastuzumab resistance.
abstract: Erbin is ubiquitously expressed in normal epithelial tissues and constitutively associates with Her2 at the basolateral membranes in epithelial cells. The inhibitory role of Erbin in ERK signaling has been demonstrated. However, whether the expression of Erbin is altered in Her2-overexpressing breast cancer is unclear. There is little information regarding the function of Erbin in cancer progression. In the present study, we demonstrate that the level of Erbin is significantly downregulated or lost in breast cancer tissues. Erbin deficiency resulted in a dramatic enhancement in heregulin-induced AKT activation and overexpression of Erbin not only significantly decreased the intensity of heregulin-induced AKT phosphorylation but also shortened its duration in Her2-overexpressing breast cancer cells. Knockdown of Erbin remarkably promotes cell migration, induces invasive phenotype of breast cancer cells and antagonized the anti-proliferative effect of therapeutic antibody trastuzumab. Treatment with AKT inhibitor GDC0941 dramatically reversed the effects of Erbin knockdown on the cell migration and trastuzumab resistance, which is mainly mediated by aberrant activation of AKT. The data reveal that Erbin is a negative regulator of AKT activation and suggest that Erbin may play a role in breast cancer progression.
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang 050017, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: Chenyang
authors.initials: C
authors.lastname: Duan
authors.forename: Hongyu
authors.initials: H
authors.lastname: Chen
authors.forename: Yabin
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Yang
authors.forename: Huijun
authors.initials: H
authors.lastname: Duan
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology; D061986:MCF-7 Cells; D020890:Neuregulin-1 / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D000068878:Trastuzumab
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D061067:Antibodies, Monoclonal, Humanized; D007191:Indazoles; D020890:Neuregulin-1; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; D000068878:Trastuzumab; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C413364:ERBIN protein, human