ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis
Thomas Worzfeld, Jakub M. Swiercz, Mario Looso, Beate K. Straub, Kishor K. Sivaraj, Stefan Offermanns
Thomas Worzfeld, Jakub M. Swiercz, Mario Looso, Beate K. Straub, Kishor K. Sivaraj, Stefan Offermanns
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Research Article Oncology

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

Thomas Worzfeld, Jakub M. Swiercz, Mario Looso, Beate K. Straub, Kishor K. Sivaraj, Stefan Offermanns

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Figure 4

Plexin-B1 is activated in ErbB-2–positive human breast cancer, and its expression level correlates with prognosis of patients.

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Plexin-B1 is activated in ErbB-2–positive human breast cancer, and its e...
(A) RNA of tumor specimens from breast cancer patients without detectable ErbB-2 expression (ErbB-2 score 0) or with ErbB-2 overexpression (ErbB-2 score 3+) was isolated and reverse transcribed. PCR analysis was performed using primers specific for Plexin-B1. (B) Immunohistochemical staining of human breast cancer tissues shows that Plexin-B1 protein is expressed in cancer cells. The staining can be blocked by preincubation of the anti–Plexin-B1 antibody (R&D Systems) with the peptide used for immunization. Scale bars: 50 μm. (C) Breast cancer tissues from 18 different patients without detectable ErbB-2 expression (ErbB-2 score 0) or different levels of ErbB-2 expression (ErbB-2 score 1+ to 3+) were lysed. Plexin-B1 was immunoprecipitated, and precipitates were immunoblotted using anti-phosphotyrosine or anti–Plexin-B1 antibodies. Lysates were probed for ErbB-2, phospho–ErbB-2(Y1248), and α-tubulin. (D) Kaplan-Meier graph representing the disease-free survival of patients with ErbB-2–overexpressing breast cancer. High Plexin-B1 expression, n = 39; low Plexin-B1 expression, n = 22. (E) Kaplan-Meier graph representing the overall survival of patients with ErbB-2–overexpressing breast cancer. High Plexin-B1 expression, n = 13; low Plexin-B1 expression, n = 7. (F) Schematic illustration of the ErbB-2/Plexin-B1 signaling pathway. Overexpression of the receptor tyrosine kinase ErbB-2 results in phosphorylation of Plexin-B1 at two specific tyrosine residues. This phosphorylation of Plexin-B1 promotes the activation of RhoA and RhoC via RhoGEF 11 (PDZ-RhoGEF) and RhoGEF 12 (LARG), which stably interact with the C terminus of Plexin-B1.