title: 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.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada H2W 1R7.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Laurin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huber
authors.forename: Ariane
authors.initials: A
authors.lastname: Pelletier
authors.forename: Tarek
authors.initials: T
authors.lastname: Houalla
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016896:Treatment Outcome; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; C099818:DOCK1 protein, human; C581047:DOCK1 protein, mouse; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse