One of the hallmarks of breast cancer is the hyperactivation of ErbB receptor signaling. The human ErbB family of tyrosine-kinase (TK) receptors consists of 4 members: ErbB1 (EGFR/HER1), the orphan receptor ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). The combinatorial dimerization of ErbB receptors and their distinct coupling to signaling adaptors and effectors create a complex network of signaling events that, when dysregulated, leads to uncontrolled growth and transformation [1
]. Aberrant expression of both ErbB receptors and their growth factor activators is a common feature in the progression of many cancers. In breast cancer, overexpression of ErbB2 and ligands such as TGFα (ErbB1 ligand) or heregulins/neuregulins (ErbB3/ErbB4 ligands) occurs with high frequency [3
]. Genetic abnormalities associated with breast cancer also include gain-of-function mutations of ErbB effectors, such as PI3KCA
gene mutations or PTEN
It is well established that members of the Rho family of small GTP-binding proteins mediate ErbB responses. Rac GTPases have been widely implicated in actin cytoskeleton reorganization, migration, mitogenesis, transformation, and metastasis [6
]. Rac inhibition impairs breast cancer cell motility and proliferation in response to EGFR and ErbB3 ligands [7
]. The activity of Rac is mainly regulated by Guanine nucleotide Exchange Factors (Rac-GEFs), which activate Rac by promoting the exchange of GDP by GTP, Guanine nucleotide Dissociation Inhibitors (GDIs), which limit the access of Rac to GEFs, and GTPase Activating Proteins (GAPs), which lead to Rac inactivation by accelerating its intrinsic GTPase activity [6
]. TK receptors can signal through multiple mechanisms to Rac-GEFs. Most notably, many Rac-GEFs depend on the PI3K product PIP3
for their redistribution to membranes and activation [10
]. Unlike Ras proteins, gain-of-function mutations in Rho GTPases are uncommon in cancer; however, there is ample evidence for hyperactivation of the Rac pathway in human cancer. For example, Rac-GAPs are down-regulated in human breast tumors [11
], and aberrant overexpression of Rac-GEFs contributes to cancer progression and metastasis in various cancer types, including breast cancer [12
]. The Rac effector Pak1 is also hyperactive in human breast tumors and promotes anti-estrogen resistance [14
]. Dissecting the cellular mechanisms leading to dysregulation of the Rac pathway in breast cancer is therefore highly relevant. Nonetheless, the relevance of Rac-GEFs in breast cancer progression remains elusive.
Here we report the identification of phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor-1 (P-Rex1) as an essential mediator of ErbB receptor-driven Rac responses in breast cancer models. Signals from ErbB receptors and GPCRs converge on P-Rex1 to mediate Rac1 activation. Notably, there is a remarkable up-regulation of P-Rex1 in human breast tumors, thus underscoring the potential prognostic and therapeutic implications of these findings.