Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis.

Abstract

Progression of solid tumors to the metastatic stage is accountable for the majority of cancer-related deaths. Further understanding of the molecular mechanisms governing metastasis is essential for the development of antimetastatic regimens. Here, we aimed to identify Rac activators that could promote metastasis downstream of human epithelial growth factor receptor 2 (HER2). We investigated if Dedicator of Cytokinesis 1 (DOCK1), based on its evolutionarily conserved role in receptor tyrosine kinases (RTKs)-mediated Rac activation and cell invasion, could be a regulator of metastasis. We report that high expression of DOCK1 in HER2(+) and basal breast cancer subtypes inversely correlates with human patients' survival. Mechanistically, DOCK1 interacts with HER2 and promotes HER2-induced Rac activation and cell migration. To gain further insight, we developed a HER2 breast cancer mouse model with mammary-gland-specific inactivation of DOCK1. In this in vivo model, a significant decrease in tumor growth and metastasis in lungs was found in animals where DOCK1 is inactivated. Furthermore, we found that DOCK1 is required for maximal activation of two HER2 effectors, c-JUN and STAT3. Using an unbiased gene profiling approach, we identified a mammary tumor DOCK1-associated gene signature enriched for genes implicated in response to IFN type I. This analysis revealed a unique set of genes, including Receptor Transporter Protein 4 (RTP4) and STAT1, for which the expression levels can be used to independently predict breast cancer outcome in HER2(+) patients. Our work demonstrates DOCK1-Rac signaling as an HER2 effector pathway essential for HER2-mediated breast cancer progression to metastasis and offers a therapeutic opportunity to limit the spread of metastatic breast cancers.

• Authors: Mélanie Laurin, Jennifer Huber, Ariane Pelletier, Tarek Houalla, Morag Park, Yoshinori Fukui, Benjamin Haibe-Kains, William J Muller, Jean-François Côté
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 18 Pg. 7434-9 (Apr 30 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23592719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DOCK1 protein, human
• DOCK1 protein, mouse
• Guanine Nucleotide Exchange Factors
• Neuregulin-1
• ERBB2 protein, human
• Erbb2 protein, mouse
• Receptor, ErbB-2
• rac GTP-Binding Proteins
• rho GTP-Binding Proteins

Topics

• Animals
• Breast Neoplasms (enzymology, genetics, pathology)
• Cell Movement
• Cell Proliferation
• Cell Transformation, Neoplastic
• Disease Models, Animal
• Enzyme Activation
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Guanine Nucleotide Exchange Factors (metabolism)
• Humans
• Lung Neoplasms (secondary)
• Mice
• Neuregulin-1 (metabolism)
• Prognosis
• Receptor, ErbB-2 (metabolism)
• Treatment Outcome
• rac GTP-Binding Proteins (metabolism)
• rho GTP-Binding Proteins (metabolism)