PtdIns(3,4,5)P <sub>3</sub> -dependent Rac exchanger 1 (P-Rex1) promotes mammary tumor initiation and metastasis
Nuthasuda Srijakotre, Heng-Jia Liu, Max Nobis, Joey Man, Hon Yan Kelvin Yip, Antonella Papa, Helen E. Abud, Kurt I. Anderson, Heidi C. E. Welch, Tony Tiganis, Paul Timpson, Catriona McLean, Lisa M. Ooms, Christina A. Mitchell
Abstract
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.