ABSTRACT
The mechanisms by which TGF-ß promotes lung adenocarcinoma (ADC) metastasis are largely unknown. Here, we report that in lung ADC cells, TGF-ß potently induces expression of DOCK4, but not other DOCK family members, via the Smad pathway and that DOCK4 induction mediates TGF-ß's prometastatic effects by enhancing tumor cell extravasation. TGF-ß-induced DOCK4 stimulates lung ADC cell protrusion, motility, and invasion without affecting epithelial-to-mesenchymal transition. These processes, which are fundamental to tumor cell extravasation, are driven by DOCK4-mediated Rac1 activation, unveiling a novel link between TGF-ß and Rac1. Thus, our findings uncover the atypical Rac1 activator DOCK4 as a key component of the TGF-ß/Smad pathway that promotes lung ADC cell extravasation and metastasis.
Subject(s)
Adenocarcinoma/physiopathology , GTPase-Activating Proteins/metabolism , Lung Neoplasms/physiopathology , Signal Transduction , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolism , Adenocarcinoma of Lung , Animals , Cell Line, Tumor , GTPase-Activating Proteins/genetics , Gene Expression Regulation, Neoplastic , Humans , Mice , Neoplasm MetastasisABSTRACT
Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer in women and lacks an effective targeted therapy. Therefore, finding common vulnerabilities in these tumors represents an opportunity for more effective treatment. Despite the growing appreciation of G-protein-coupled receptor (GPCR)-mediated signaling in cancer pathogenesis, very little is known about the role GPCRs play in TNBC. Using genomic information of human breast cancer, we have discovered that the orphan GPCR, G-protein-coupled receptor 161 (GPR161) is overexpressed specifically in TNBC and correlates with poor prognosis. Knockdown of GPR161 impairs proliferation of human basal breast cancer cell lines. Overexpression of GPR161 in human mammary epithelial cells increases cell proliferation, migration, intracellular accumulation of E-cadherin, and formation of multiacinar structures in 3D culture. GPR161 forms a signaling complex with the scaffold proteins ß-arrestin 2 and Ile Gln motif containing GTPase Activating Protein 1, a regulator of mammalian target of rapamycin complex 1 and E-cadherin. Consistently, GPR161 amplified breast tumors and cells overexpressing GPR161 activate mammalian target of rapamycin signaling and decrease Ile Gln motif containing GTPase Activating Protein 1 phosphorylation. Thus, we identify the orphan GPCR, GPR161, as an important regulator and a potential drug target for TNBC.
