PtdIns(3,4,5)P3-dependent Rac exchanger 1 (P-Rex1) promotes mammary tumor initiation and metastasis

Significance Breast cancer is the most common cancer in women and metastasis remains the leading cause of death. P-Rex1, a guanine nucleotide exchange factor, positively regulates Rac1-mediated oncogenic signaling. P-Rex1 is overexpressed in a subset of human breast cancers; however, little is known of its function in vivo. Here we show P-Rex1 regulates Rac1 activation in vivo in the mammary gland. Increased P-Rex1 expression enhances mammary epithelial cell proliferation and is causally associated with tumor initiation. In murine models, P-Rex1 cooperates with the neu oncogene to increase mammary tumor incidence and metastasis but not primary tumor growth. Our studies suggest that inhibiting the P-Rex1–Rac1 signaling axis may be an adjunct therapy for treating invasive cancers which exhibit increased P-Rex1 expression. The Rac-GEF, P-Rex1, activates Rac1 signaling downstream of G protein-coupled receptors and PI3K. Increased P-Rex1 expression promotes melanoma progression; however, its role in breast cancer is complex, with differing reports of the effect of its expression on disease outcome. To address this we analyzed human databases, undertook gene array expression analysis, and generated unique murine models of P-Rex1 gain or loss of function. Analysis of PREX1 mRNA expression in breast cancer cDNA arrays and a METABRIC cohort revealed that higher PREX1 mRNA in ER+ve/luminal tumors was associated with poor outcome in luminal B cancers. Prex1 deletion in MMTV-neu or MMTV-PyMT mice reduced Rac1 activation in vivo and improved survival. High level MMTV-driven transgenic PREX1 expression resulted in apicobasal polarity defects and increased mammary epithelial cell proliferation associated with hyperplasia and development of de novo mammary tumors. MMTV-PREX1 expression in MMTV-neu mice increased tumor initiation and enhanced metastasis in vivo, but had no effect on primary tumor growth. Pharmacological inhibition of Rac1 or MEK1/2 reduced P-Rex1-driven tumoroid formation and cell invasion. Therefore, P-Rex1 can act as an oncogene and cooperate with HER2/neu to enhance breast cancer initiation and metastasis, despite having no effect on primary tumor growth.