title: ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis.
abstract: Diagnosis of metastatic breast cancer is associated with a very poor prognosis. New therapeutic targets are urgently needed, but their development is hampered by a lack of understanding of the mechanisms leading to tumor metastasis. Exemplifying this is the fact that the approximately 30% of all breast cancers overexpressing the receptor tyrosine kinase ErbB-2 are characterized by high metastatic potential and poor prognosis, but the signaling events downstream of ErbB-2 that drive cancer cell invasion and metastasis remain incompletely understood. Here we show that overexpression of ErbB-2 in human breast cancer cell lines leads to phosphorylation and activation of the semaphorin receptor Plexin-B1. This was required for ErbB-2-dependent activation of the pro-metastatic small GTPases RhoA and RhoC and promoted invasive behavior of human breast cancer cells. In a mouse model of ErbB-2-overexpressing breast cancer, ablation of the gene encoding Plexin-B1 strongly reduced the occurrence of metastases. Moreover, in human patients with ErbB-2-overexpressing breast cancer, low levels of Plexin-B1 expression correlated with good prognosis. Our data suggest that Plexin-B1 represents a new candidate therapeutic target for treating patients with ErbB-2-positive breast cancer.
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Worzfeld
authors.forename: Jakub M
authors.initials: JM
authors.lastname: Swiercz
authors.forename: Mario
authors.initials: M
authors.lastname: Looso
authors.forename: Beate K
authors.initials: BK
authors.lastname: Straub
authors.forename: Kishor K
authors.initials: KK
authors.lastname: Sivaraj
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
mesh_terms: D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D011499:Protein Processing, Post-Translational; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000502:physiology
chemical_list: D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; D020741:rho GTP-Binding Proteins; C492119:PLXNB1 protein, human; C492118:Plxnb1 protein, mouse