Increased Expression Levels of WAVE3 Are Associated with the Progression and Metastasis of Triple Negative Breast Cancer

Abstract

BackgroundBreast Cancer (BC) is a heterogeneous disease comprised of at least five genetically distinct subtypes, which together form the second leading cause of cancer death in women in the United States. Within BC subtypes, those classified as Triple Negative BCs (TNBCs) exhibit dismal survival rates due to their propensity to develop distant metastases. We have identified the WAVE3 protein, which is a critical regulator of actin cytoskeleton dynamics that are required for the motility and invasion of cancer cells through its activation of the Arp2/3 complex, as a key regulator of the different steps of the invasion-metastasis cascade in BC, especially in the more aggressive TNBCs. Our published studies have also shown that elevated expression levels of WAVE3 in the TNBC cell lines directly contribute to their increased invasion and metastasis potentials both in vitro and in vivo in murine models of BC metastasis.Methodology/Principal FindingsHerein, we utilized both immunohistochemistry (IHC) of primary human BC tumors as well as quantitative real-time RT-PCR of WAVE3 in the peripheral blood of BC patients to clearly establish that WAVE3 is a predictive marker of overall BC patients’ survival. High levels of WAVE3 were predictive for reduced distant recurrence-free survival as well as for decreased disease-specific mortality. Our analysis of WAVE3 expression levels in the peripheral blood of BC patients showed that WAVE3 is highly expressed in the blood of patients who developed metastatic breast cancer compared to those who did not. WAVE3 expression was also highly upregulated in the blood of BC patients with the more aggressive TNBC subtype.ConclusionsTogether, these findings establish WAVE3 as a novel marker for increased risk of breast-cancer-specific mortality and for the metastatic potential of the TNBCs, and also identify WAVE3 as an attractive therapeutic target for the treatment of metastatic BC.

Loss of WAVE3 sensitizes triple-negative breast cancers to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis

“…9 WAVE3 belongs to the WASP/WAVE family of actin-binding proteins that play broad roles in regulating cell shape/morphology, actin polymerization, and cytoskeleton remodeling, all of which are coupled to cell motility and invasion. [26][27][28][29][30][31][32][33][34] We demonstrated the necessity of WAVE3 expression to drive the invasion and metastasis of human TNBCs in part by stimulating: (i) expression of MMPs 1, 3, and 9; (ii) formation of invadopodia; and (iii) activation of p38 MAPK. [27][28][29][30][31][32]35 Moreover, we also identified WAVE3 as a novel substrate for the nonreceptor protein kinase c-Abl.…”

“…cDNA was generated and used as a template for quantitative RT-PCR performed as previously described. 26,33 qRT-PCR was performed using the respective gene-specific primers (SABiosciences, Valencia, CA) and the RT Flow cytometry MDA-MB-231 or BT549 cells, transfected with either the control non-targeting shRNA or the shWAVE3, were propagated in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% FBS and puromycin (5 mg/mL). Subconfluent cell cultures were treated with either the diluent or doxorubicin (50 nM), or docetaxel (5 nM) for 12 h, after which cells were detached by trypsinization and washed with Hank's Balanced Salt Solution with Ca 2C , Mg2C, and 0.1% BSA.…”

“…33,34,36,37 Clinically, aberrant WAVE3 expression is a strong indicator of human BC progression, as well as predictor for TNBC size, stage, and lymph node metastasis. 26,38 We have found that WAVE3 expression levels determine the sensitivity of TNBC cells to apoptosis and cell death driven by TNFa, 35 as knockdown of WAVE3 by siRNA or shRNA approaches enhances susceptibility of MDA-MB-231 TNBC cells to the TNFa-driven apoptosis and cell death. 35 How WAVE3 drives chemoresistance in TNBC, however, remains poorly understood.…”

WAVE3 promotes epithelial–mesenchymal transition of gastric cancer through upregulation of Snail

“…These data strongly suggest that improving the expression of WAVE3 in SGC-7901 cells could promote the migration and invasion ability SGC-7901 cells in vitro. 17 Upregulating WAVE3 promoted gastric-cancer cells proliferation in vitro Along with cell invasion and metastasis, proliferation ability was also required for cancer progression, invasion and metastasis. To Figure 4a and b).…”

“…13 WAVE3, a member of the WASP (Wiskott-Aldrich syndrome protein)/WAVE actin cytoskeleton remodeling family of proteins, is critical for the motility, migration and invasive properties of cancer cells. 14 More importantly, Taylor et al 15 reported in 2013 that WAVE3 expression is required in mediating the initiation of EMT programs stimulated by TGF-β. They also suggested that measures capable of inactivating WAVE3 may have a role in alleviating metastasis stimulated by TGF-β.…”