Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs

Abstract

Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide-exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer.

Keywords: Cdc42; breast cancer; cytoskeleton remodeling; non-coding RNAs; targeted therapy; tumor progression.

Figure 1

Cdc42 regulates breast cancer cell proliferation. Hyperactivated Cdc42 through p85Cool-1/β-Pix impedes c-Cbl binding to EGFR, results in EGFRs escaping from catalyzing receptor ubiquitination. Through EGFR signaling, Cdc42 induces overexpression of Ack1. Constitutive activation of Ack1 can recruit AKT to the cell membrane and subsequently activate AKT to promote breast cancer progression. A positive feedback loop exists between EGFR and Cdc42 and that EGFR is able to stimulate Cdc42 activation. Cdc42 can also interact with aPKC, overexpressed Par6, PAK, IQGAP1 and procathepsin D to promote breast cancer cell growth in a MAPK/ERK-dependent manner. Besides, Cdc42 induces p53 ubiquitination to overcome cell growth inhibition. In ER-positive MCF-7 breast cancer cells, S100A7 inhibits NF-κB. In ER-negative MDA-MB-231 cells, S100A7 activates NF-κB. NF-κB can decrease the levels of miR-29b directly or through YY1. Decreased miR-29b cannot inhibit Cdc42/p53 signaling, thus to promote breast cancer cells proliferation.

Figure 2

Role of Cdc42 on regulation of migratory protrusions formation. Model of lamellipodia formation: cofilin severs pre-existing actin filaments to produce free barbed ends. The Src/FAK complex activates Paxillin to recruit Cdc42 and trigger N-WASP activation. The combination of activated N-WASP with Arp2/3 leads to actin nucleation of new filaments at the cofilin-severed barbed ends. Cdc42 activates formins. Profilin delivers G-actin to formins to extend filaments. Rac interacts with lamellipodin that binds with WAVE to extend actin filaments. Model of filopodia formation: IRSp53 recruits Cdc42 and mDia2. mDia2 mediates actin nucleation. VASP delivers actin monomers to the filopodial tip and G-actin is provided directly to mDia2 by duringilin. Cdc42 and Rif can regulate actin polymerization by targeting mDia2. Cdc42 can also stimulate N-WASP/Arp2/3-driven polymerization. Model of invadopodia formation: Cdc42 and RhoA trigger the interaction of IQGAP1 with the exocyst subunits Sec3 and Sec8, which is necessary for invadopodia activity. MT1-MMP is transported to the tip of invadopodia by microtubule-mediated vesicle trafficking to degrade the extracellular matrix.

Figure 3

Cdc42 modulates the establishment of cell polarity. Establishment of single-cell polarity: Activated Rac1 and Cdc42 mark spots where IQGAP1 tethers actin filaments. IQGAP1 links APC to actin filaments and captures the plus-ends of microtubules through the microtubule-binding protein CLIP-170, which stabilizes microtubules and generates a stable actin meshwork at the leading edge. Cdc42 regulates the reorientation of the MTOC via a Par6/aPKC complex to induce the phosphorylation of GSK-3β. Maintenance of collective polarity: Strong cell-cell adhesion is established when the increasingly active Rac1 and Cdc42 interact with IQGAP1 to crosslink actin filaments.