Identification of the Rac-GEF P-Rex1 as an Essential Mediator of ErbB Signaling in Breast Cancer

Abstract

SUMMARY While the small GTPase Rac1 and its effectors are well-established mediators of mitogenic and motile signaling by tyrosine-kinase receptors and have been implicated in breast tumorigenesis, little is known regarding the exchange factors (Rac-GEFs) that mediate ErbB receptor responses. Here we identify the PIP3-Gβγ-dependent Rac-GEF P-Rex1 as an essential mediator of Rac1 activation, motility, cell growth, and tumorigenesis driven by ErbB receptors in breast cancer cells. Notably, activation of P-Rex1 in breast cancer cells requires the convergence of inputs from ErbB receptors and a Gβγ- and PI3Kγ-dependent pathway. Moreover, we identified the GPCR CXCR4 as a crucial mediator of P-Rex1/Rac1 activation in response to ErbB ligands. P-Rex1 is highly overexpressed in human breast cancers and their derived cell lines, particularly those with high ErbB2 and ER expression. In addition to the prognostic and therapeutic implications, our findings reveal an ErbB effector pathway that is crucial for breast cancer progression.

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

“…S2 C and D). HRG-mediated activation of HER2 is reported to activate Rac and increase cell motility (8). To examine whether DOCK1 can facilitate HRG-induced Rac activation and cell migration, its GEF activity was inhibited via a small molecule, 4-[3′-(2″-chlorophenyl)-2′-propen-1′-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) (15).…”

“…Interestingly, systemic inactivation of the RacGEF TIAM1 was reported to protect mice from Neu-induced tumors, suggesting a role in cell survival in vivo (24). P-REX1 was identified as a GEF mediating Rac activation in luminal breast cancer cells upon HRG stimulation (8). DOCK1 and P-REX1 share similarities as they are recruited to the membrane by Phosphatidylinositol 3,4,5-trisphosphate and can act downstream of G protein coupled receptors to mediate Rac activation in migrating cells (8,25).…”

“…P-REX1 was identified as a GEF mediating Rac activation in luminal breast cancer cells upon HRG stimulation (8). DOCK1 and P-REX1 share similarities as they are recruited to the membrane by Phosphatidylinositol 3,4,5-trisphosphate and can act downstream of G protein coupled receptors to mediate Rac activation in migrating cells (8,25). P-REX1 is likely to be involved in luminal and estrogen receptor positive breast cancer progression according to its expression profile (8).…”

“…Rac promotes mesenchymal cell movement (7), but also contributes to cell proliferation and survival. Whereas HER2 can activate Rac in cell lines (8), the exact guanine exchange factors (GEFs) responsible for its activation downstream of HER2 remain poorly defined in vivo. The Dedicator of Cytokinesis 1 (DOCK1) family GEFs are an important class of cytoskeletal regulators controlling cell migration (9).…”

Infectivity and insertional mutagenesis of endogenous retrovirus in autoimmune NZB and B/W mice

“…According to the UCSC Genome Browser, the protein is strongly expressed in brain, trachea, thymus, bone marrow, and B-and T-cells. Prex1 is also overexpressed in prostate cancer (Knight-Krajewski et al, 2004) and breast cancer (Sosa et al, 2010). In addition, patients whose tumours express Prex1 are more likely to develop metastasis, when compared with those whose tumours do not express Prex1 (Sosa et al, 2010).…”