ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis
Thomas Worzfeld, … , Kishor K. Sivaraj, Stefan Offermanns
Thomas Worzfeld, … , Kishor K. Sivaraj, Stefan Offermanns
Published March 1, 2012
Citation Information: J Clin Invest. 2012;122(4):1296-1305. https://doi.org/10.1172/JCI60568.
View: Text | PDF
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

×

Figure 3

Plexin-B1 promotes metastasis in a mouse model of ErbB-2–overexpressing breast cancer.

Options: View larger image (or click on image) Download as PowerPoint
Plexin-B1 promotes metastasis in a mouse model of ErbB-2–overexpressing ...
(A) MMTVneu;Plxnb1+/+ mice (WT) and MMTVneu;Plxnb1–/– mice (KO) were examined weekly for the appearance of mammary tumors. Shown is the percentage of tumor-free survival plotted against time. WT, n = 37; KO, n = 40. (B) Eight and one half weeks after the first appearance of a palpable tumor, mice were sacrificed, and tumors were excised and weighed. Data are presented as mean ± SD. (C) Macroscopic images of the lungs of tumor-bearing MMTVneu;Plxnb1+/+ mice and MMTVneu;Plxnb1–/– mice. Metastases are indicated by arrows. (D) Quantification of the results in (C). (E) Microscopic images of H&E-stained histological sections of tumor-bearing mice. Metastases are indicated by arrows. (F and G) Lung sections of tumor-bearing mice were microscopically analyzed, and the metastases per lung (F) and metastases per histological section (G) were counted. P values in F and G refer to differences between WT and KO in all groups combined. Statistical significance was determined by log-rank test (A), t test (B, F, and G), and Fisher’s exact test (D). *P ≤ 0.05. Scale bars in E: 100 μm.