Rac signaling in breast cancer: a tale of GEFs and GAPs

Abstract

Rac GTPases, small G-proteins widely implicated in tumorigenesis and metastasis, transduce signals from tyrosine-kinase, G-protein-coupled receptors (GPCRs), and integrins, and control a number of essential cellular functions including motility, adhesion, and proliferation. Deregulation of Rac signaling in cancer is generally a consequence of enhanced upstream inputs from tyrosine-kinase receptors, PI3K or Guanine nucleotide Exchange Factors (GEFs), or reduced Rac inactivation by GTPase Activating Proteins (GAPs). In breast cancer cells Rac1 is a downstream effector of ErbB receptors and mediates migratory responses by ErbB1/EGFR ligands such as EGF or TGFα and ErbB3 ligands such as heregulins. Recent advances in the field led to the identification of the Rac-GEF P-Rex1 as an essential mediator of Rac1 responses in breast cancer cells. P-Rex1 is activated by the PI3K product PIP3 and Gβγ subunits, and integrates signals from ErbB receptors and GPCRs. Most notably, P-Rex1 is highly overexpressed in human luminal breast tumors, particularly those expressing ErbB2 and estrogen receptor (ER). The P-Rex1/Rac signaling pathway may represent an attractive target for breast cancer therapy.

Figure 1. A model for the regulation of Rac activity by GEFs and GAPs in breast cancer

ErbB receptors activate the PI3K-Gβγ-dependent P-Rex1 through transactivation of the GPCR CXCR4. Chimaerin Rac-GAPs are also regulated by ErbB receptors and act as a brake for the Rac activation.

Figure 2. The Rac signaling pathway

Rac is activated by tyrosine-kinase receptors (RTKs), GPCRs, integrins and stress. Rac activation promotes changes related to cytoskeleton reorganization (left) and other responses (right) through multiple mediators. Rac-GTP induces the activation of WAVE through either Irsp53 or Nap125-PIR121 complexes. WAVE activates Arp2/3, leading to changes in actin cytoskeleton necessary for ruffle formation and cell migration. Rac also activates PAK, which exerts its effects through Arp2/3 and LIMK activation or MLCK inhibition. In addition, Rac forms part of the NADPH oxidase complex that generates reactive oxygen species. Rac/PAK activates MAPKs implicated in stress response, mitogenesis, and survival.

Figure 3. Overexpression of P-Rex1 in breast cancer

Panel A. Expression of P-Rex1 mRNA by Q-PCR in human mammary cell lines. Values presented as “fold-increase” are relative to levels in MCF-10A cells. Panel B. Immunohistochemistry comparing P-Rex1 staining in a human breast tumor and normal mammary tissue.