Elucidating the molecular signaling pathways of WAVE3
Review Article on Cancer Metastasis Molecular Signaling and Therapeutic Options

Elucidating the molecular signaling pathways of WAVE3

Urna Kansakar1,2, Wei Wang1,2, Vesna Markovic1,2, Khalid Sossey-Alaoui1,2

1Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; 2Rammelkamp Center for Research, MetroHealth, Cleveland, OH, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: K Sossey-Alaoui; (III) Provision of study materials or patients: K Sossey-Alaoui, U Kansakar; (IV) Collection and assembly of data: U Kansakar, K Sossey-Alaoui; (V) Data analysis and interpretation: U Kansakar, W Wang, K Sossey-Alaoui; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Khalid Sossey-Alaoui, PhD. Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Rammelkamp Center for Research, MetroHealth, R457, 2500 MetroHealth Drive, Cleveland, OH 44109, USA. Email: kxs586@case.edu.

Abstract: Cancer metastasis is a complex, multistep process that requires tumor cells to evade from the original site and form new tumors at a distant site or a different organ, often via bloodstream or the lymphatic system. Metastasis is responsible for more than 90% of cancer-related deaths. WAVE3 belongs to the Wiskott-Aldrich syndrome protein (WASP) family, which regulate actin cytoskeleton remodeling as well as several aspects of cell migration, invasion, and metastasis. In fact, WAVE3 has been established as a driver of tumor progression and metastasis in cancers from several origins, including triple negative breast cancers (TNBCs), which are classified as the most lethal subtype of breast cancer, due to their resistance to standard of care therapy and highly metastatic behavior. In this review, we will attempt to summarize the recent advances that have been made to understand how WAVE3 contributes to the molecular mechanisms that control cancer progression and metastasis. We will also review the signaling pathways that are involved in the regulation of WAVE3 expression and function to identify potential therapeutic options targeted against WAVE3 for the treatment of patients with metastatic tumors.

Keywords: WAVE3; triple negative breast cancer (TNBC); metastasis

Submitted Dec 11, 2019. Accepted for publication Jan 21, 2020.

doi: 10.21037/atm.2020.02.16


The Wiskott-Aldrich syndrome protein (WASP) family includes two subfamilies, WASP (WASP and N-WASP) and WASP family verprolin-homologous WAVE proteins (WAVE1/SCAR1, WAVE2 and WAVE3) (1,2). The WASP and WAVE proteins play a major role in cell motility through the activation of filopodia and lamellipodia formation at the leading edge of migrating cells (3-7) by regulating actin polymerization through binding to the Arp2/3 protein complex (4,5,8-12). The formation of these membrane filament (filopodia) and ruffle (lamellipodia) structures is regulated by molecular switches that are a part of the Rho family of GTP-exchange factors: (RhoA, Cdc42, and Rac) (13-15). While the WASP and NWASP are regulated by Cdc42, WAVE1, 2 and 3 are regulated downstream of Rac (1,2,7,13,15,16). The WAVE regulatory complex (WRC) is a five-subunit protein complex that regulates the activity of the WAVE proteins and it plays an important role in regulating actin polymerization. The WAVE proteins were shown to be sequestered in an inactive state through the formation of a complex with the four other protein members of the WRC, PIR121, Nap125, HSPC300, and Abi1 (17-19). WRC is activated by Rho GTPase Rac1 and sends information to the actin nucleator Arp2/3 complex (20-24). Among the various WASP and WAVE proteins, WAVE3 has been established a major driver of the invasive and metastatic phenotypes in several types of cancers, including the one generating for the breast (3,25). WAVE3, like WAVE1 and WAVE2, contains several functional domains (I) an N-terminal basic region (BR); followed by (II) a proline-rich domain (PRD) that binds and activates SH2- and SH3-containing proteins kinases such as c-Abl and PI3K-p85; and (III) a verprolin-cofilin-acidic (VCA) domain that binds the Arp2/3 complex and activates actin polymerization (26). Several studies have reported that WAVE3 is found to be present on the leading edge and in the tips of pre-mature and mature filopodia (11,16). This was also demonstrated by immunostaining the filopodia with anti-WAVEs and actin filaments with rhodamine (16). However, WAVE3 is distributed in a discrete manner on the leading edge of lamellipodia and tips of filopodia (27) as opposed to WAVE1 which demonstrated continuous distribution (16). High WAVE3 expression is related to cancer invasion and metastasis (9,28). Loss of WAVE3 inhibits the formation of invadopodia (27), thereby further inhibiting cell migration, invasion, and extracellular matrix (ECM) degradation (5). Ji et al. (29) showed that knockdown of WAVE3 inhibits cell migration and invasion in hepatocellular carcinoma (HCC) cells. WAVE3 is largely concentrated in the nucleus and cytoplasm (6). It is found to be upregulated in breast (27), prostate (15), liver (3,29), pancreas (30), and ovarian cancers. Furthermore, it was shown that WAVE3 is co-localized with actin structures in the lamellipodia (6). Reports have shown that WAVE3 protein levels are correlated to different grades of tumor (5,8,31). However, the expression of WAVE3 varies with cell lines. For example, Taylor et al. (32) demonstrated that there was high expression of WAVE3 in breast cancer cell lines such as MDA-MB 231 and BT-549. Similarly, the expression of WAVE3 was upregulated in PANC-1, a pancreatic cancer cell line (30). In another study, Lu et al. (31) showed that SKOV3 cells showed highest WAVE3 expression among five different human ovarian cancer cell lines whereas A2780 had the lowest expression. The expression levels of WAVE3 upregulated in HCC tissues than adjacent non-cancerous tissues. It was also demonstrated that silencing WAVE3 causes decreased expression of COX-2, VEGF, nuclear factor-kappa B (NFκB) and p38 mitogen-activated protein kinase (MAPK) in SKOV3 cells and elevated expression causes high expression of the same in A2780 cells (31).

One of the tumors where WAVE3 has been heavily investigated is breast cancer. Breast cancer is the second leading cause of cancer-related deaths in women in the United States and worldwide (32-35). Breast cancer causes more than 40,000 deaths in the United States annually (33,36,37). The most abysmal type of breast cancer is triple negative breast cancer (TNBC) which is also disproportionally higher in the African-American population (38-41). Cancer metastasis requires tumor cells to evade from a primary site and form new tumors at a distant site or a different body part, often via bloodstream or the lymphatic system (5,8,9,42,43). Almost 90% of deaths are caused due to metastases (32,44-46). TNBC cells lack estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) (32,47-52). Due to the highly metastatic behavior of these tumors, they are classified as the most lethal subtype of breast cancer (32,33,36). Cancer stem cells (CSCs) have been involved in tumor initiation, development, and metastatic dissemination, especially in TNBCs. They exhibit resistance to chemotherapy and radiotherapy and are capable of self-renewal, often causing recurrence (53-56). Reports have shown that WAVE3 is enriched in the population of CSCs and silencing WAVE3 might reduce chemoresistance in TNBC cells (36).

In this review, we will discuss about the advances made in WAVE3 in the last few decades. We believe that targeting WAVE3 can be one of the approaches for potential therapeutic strategies for treating patients with cancer, especially breast cancer.

Genetic approaches to target WAVE3 expression and activity in cancer cells

There are different approaches to target a specific protein: direct biochemical methods, genetic interaction and genomic methods, and computational inference methods (57). In this section, we describe the various approaches that have been used to successfully target and inhibit WAVE3. Ji et al. (29) reported using short interfering RNAs (siRNA) targeting of WAVE3 in HepG2 cells. The expression of WAVE3 protein significantly decreased in si-WAVE3 transfected HepG2 cells than controls. Similarly, Zhu et al. (3) found out that the WAVE3 protein significantly decreased after using siRNA to knockdown the proteins in another liver carcinoma cell line, CC-LP-1 cells. All characteristics of a tumor cells such as migration, invasion and proliferation were inhibited after the WAVE3 knockdown using siRNAs (3). The siRNA-mediated knockdown of gene expression is, however, transient since the knockdown effect cannot be sustained beyond 96–120 hours post transfection. Therefore, long-term biological effect of gene knockdown cannot be assessed using siRNAs, including in vivo effects. Accordingly, Lu et al. (31) used short hairpin RNA (shRNA) technique to knockdown WAVE3 in ovarian cancer cells. In another study, Sossey-Alaoui et al. (5) used shRNA to overcome the limitation of siRNA. Stable shRNA-mediated WAVE3 knockdown in human MDA-MB-231 and murine 4T1 breast cancer cells was found to significantly inhibit tumor growth and metastasis in mouse models for breast cancer (36). In another study, knockdown of WAVE3 in PC-3 and DU-145 prostate cancer cell lines was carried out using ribozyme transgene method (15,58). The authors also demonstrated that there was a decrease in invasion of the cells after WAVE3 was knocked down using this method. Both studies reported that this technique did not affect the cell adhesion with matrix whereas invasion through Matrigel decreased significantly (8).

CRISPR/Cas9 technology has been used as an efficient and versatile tool to permanently target and edit specific gene at precise locations. CRISPR/Cas9 has proved to be competent than other prevailing gene editing approaches such as siRNA and shRNA. Bledzka et al. (36) used CRISPR/Cas9-mediated knockout of WAVE3 where single-guide RNAs (sgRNAs) were used to target exon 2 and exon 3 of the human WAVE3 gene. The number of invadopodia formed and the total area of ECM degradation decreased significantly in WAVE3 knockout cells compared to control (Scram CRISPR) MDA-MB 231.

Another technique to target WAVE3 is achieved by genetic knockdown of CYFIP1 with stapled peptides known as WASF helix mimics (WAHM). Genetic knockdown of CYFIP1 eventually reduces WAVE3 levels, preventing the invasion. Peptide-mediated inhibition of WAVE3 could be a promising therapeutic approach for suppressing tumor invasion and metastasis. However, the level of suppression of invasion by this method is not as much of as compared to the shRNAs (46). Taken together, these studies suggest that the genetic approaches used to knockdown WAVE3 causes inhibition of invasion and migration of cells.

WAVE3 and microRNAs

Small non-coding RNA molecules, also known as microRNAs, are responsible for RNA silencing and post-transcriptional regulation of gene expression (28,59,60). Out of all the miRNAs, nine of them are tumor suppressive in breast cancer. They are miR-30a, miR-30c, miR-31, miR-126, miR-140, miR146b, miR200c, miR-206, and miR-335 (61). miR200 microRNAs are responsible for the expression of WAVE3 protein and regulation of epithelial-mesenchymal transition (EMT) during tumor progression and metastasis (8). WAVE3 expression is suppressed when the miR200 directly targets the 3’-untranslated regions. Invasive and non-invasive cancer cells showed that miR200 and WAVE3 are inversely correlated (28). Mesenchymal cell types such as MDA-MB 231 and PC-3 do not express miR200 whereas epithelial cell types such as MCF7 and HT29 shows overexpression of miR200 (28). Moreover, there is a decrease in miR-200c because of loss of p53. However, loss of WAVE3 causes increase in p53 levels. On the other hand, the downstream protein of p53, Bcl-2 was decreased because of inhibition by p53. It has been reported that downregulation of microRNA miR-31, a metastasis suppressor gene (59), promotes invasion-metastasis cascade (28,60). Furthermore, Sossey-Alaoui et al. (8) also showed that there is an inverse correlation between WAVE3 and miR-31 expression level, especially in human breast cancers.

WAVE3 and matrix metalloproteinases (MMPs)

MMPs have been found to be involved in cell invasion and migration (27,62) and they are an essential part of invadopodia (27). MMPs are enzymes that are involved in the breakdown of ECM. Malignant cells use MMPs to enzymatically degrade the ECM through p38 MAPK pathway to facilitate invasion and metastasis (9,63). MMPs play a vital role in different steps of tumor growth and metastasis, angiogenesis, and wound healing (64,65). Previous studies have demonstrated that averting metastasis is possible by targeting and inhibiting the MMPs activity (31). Nuclear factor NFkB, a protein complex involved in invasion and metastasis of cancer, plays a key role in the production of MMPs (MMP-1, MMP-3, and MMP-9) (66). Loss of WAVE3 does not affect MMP-2 but inhibits the expression levels of MMP-1, MMP-3, and MMP-9 (7). However, treatment with MMP activator phorbol myristate acetate (PMA) can bring back the MMP production without altering siRNA-mediated WAVE3 knockdown. Moreover, downregulation of p38 and MMP production is mediated by WAVE3 (7). Low expression of MMP-2 and MMP-9 was observed after WAVE3 knockdown in SKOV3 cells whereas the expression of MMP-2 and MMP-9 was high in A2780 cells. Similarly, there was low expression of MMP-2 in PC-3 cells (58). Further, knockdown of WAVE3 phosphorylation causes decrease in MMP-2 and MMP-9 activity (27).

Pathways contributing to cancer progression and metastasis

WAVE3 and c-Abl

c-Abl, a non-receptor tyrosine kinase, is found in the nucleus and cytoplasm. c-Abl is responsible for the regulation of cell motility and localization of focal adhesions and lamellipodia (67). Sossey-Alaoui et al. (4) showed that WAVE3 is downstream of c-Abl tyrosine kinase. Further, treatment with platelet-derived growth factor (PDGF) causes phosphorylation of WAVE3 (6). Interaction of WAVE3 with Ableson (Abl) non-receptor tyrosine kinase promotes the tyrosine phosphorylation. On the other hand, the Abl-mediated phosphorylation of WAVE3 is blocked by STI-571, a specific inhibitor of Abl kinase activity (4). Both WAVE3-Abl interaction and Abl-kinase activity are necessary for the Abl-mediated phosphorylation of WAVE3 (28).

WAVE3 and phosphatidylinositol 3-kinase (pI3K)

Phosphatidylinositol 3-kinases (PI3Ks), also known as phosphoinositide 3-kinases, are enzymes that regulates cellular functions like cell growth, motility, and survival (68,69). PI3K signaling pathway is found to be dysregulated in almost all cancers, including breast cancer (70,71). Targeting this pathway can be a potential therapeutic option for treating TNBC patients (72,73). Reports have shown that PI3K is upstream of WAVE3 (6). Sossey-Alaoui et al. (5) demonstrated that knockdown of WAVE3 using siRNA decreases the ability to form lamellipodia at the migrating edge of breast cancer cells. Moreover, LY294002, an inhibitor of PI3K, prevents the formation of lamellipodia and cell migration. Thus, PI3K is essential for WAVE3 activity (6). Further, lamellipodia formation and WAVE3-mediated cell motility in breast cancer cell line (MDA-MB-231) is induced by PDGF which was confirmed by wound healing and migration assays. It was further reported that knockdown of WAVE3 using the same technique causes inhibition in the formation of PDGF-induced lamellipodia in breast cancer cells (6). Direct physical interaction of p85, the regulatory subunit of PI3K, with WAVE3 may be required for WAVE3-mediated lamellipodia formation, cell migration, and invasion. This interaction is facilitated by the BR domain of WAVE3 and the C-terminal SH2 domain of p85. Thus, it is confirmed that PI3K is imperative for the regulation of WAVE3-mediated lamellipodia formation and cell migration (6).

WAVE3 and AKT pathway

Protein kinase B (AKT) has been implicated in a variety of cellular functions such as cell proliferation and migration (74,75). AKT is a downstream effector of PI3K (76). PI3K plays a role in cancer progression and metastasis through both AKT-dependent and AKT-independent mechanisms (77). Inhibition of AKT prevents the formation of invadopodia in breast cancer cells (9,76). There is an increase in phosphorylation of AKT due to overexpression of WAVE3. Knockdown of WAVE3 does not affect the AKT, ERK 1/2, or JNK. NFKB activates AKT signaling and if the AKT is inhibited using AKT inhibitor (MK-2206), NFKB is negatively affected (13). This was proved by treating MDA-MB-231 cells with MK-2206, whereby, there was a significant reduction in phospho-AKT and phospho-p65 whereas total AKT or total p65 levels were not affected (9).

WAVE3 and transforming growth factor-β (TGF-β)

TGF-β, a multifunctional cytokine (32), plays a dual role in breast cancer, acting both as a tumor-promotor and tumor suppressor (78-80). It has been reported that high TGF-β contributes to tumor suppression during early stages of tumor. On the other hand, they lose the growth inhibitory effect, become malignant and aid in promoting tumor towards the later stages (79,81,82). However, the switch of TGF-β from tumor suppressor to tumor promoter remains unelucidated (83,84). Reports have shown that p53 is involved in the switch of TGF-β from tumor suppressor in pre-malignant cells to tumor promotor in cancer cells (83). The tumor suppressor protein p53 inhibits TGF-β induced EMT through activation of miR-200c (85). Taylor et al. (32) found out that TGF-β is upstream of WAVE3 and there was an upregulation of WAVE3 by TGF-β in metastatic breast cancer cells (MDA-MB-231 and BT549). However, there was only a slight upregulation detected in non-metastatic cells (MCF7 and T47D). TGF-β receptors not only activate Smads, but they activate other signaling pathways as well. Activation of several receptors such as epidermal growth factor (EGF) through signal transducer and activator of transcription (STAT) and NFkB by tumor necrosis factor-α (TNF-α) causes inhibition of TGF-β (86). Taylor et al. (32) further reported that Smad2 and β3 integrin are important to induce WAVE3 expression in TNBCs by TGF-β.

WAVE3-p38 pathway

p38 MAPKs belongs to the MAPK family and they are responsible for regulating cellular activities such as proliferation, differentiation, migration, and survival (87-89). They are activated by cellular stress and cytokines. TGF-β activates other signaling pathways such as p38 MAPK pathway (86,90). Knockdown of WAVE3 expression using siRNAs causes decrease in cell motility and metastasis-invasion cascade, especially in breast cancer cells. Further, there was a decrease in p38 MAP kinase phosphorylation because of downregulation of WAVE3. Further, it was interesting to note that WAVE3-mediated downregulation of p38 activity does not alter the expression levels of WAVE1 and WAVE2 genes even after knockdown of WAVE3 (7,28). Studies have reported that p38 MAPK is downstream of WAVE3 in cell migration and invasion (5,7). Sossey-Alaoui et al. (7) further demonstrated that knockdown of WAVE3 decreases phosphorylation levels of p38 MAPK levels whereas the activity of AKT, ERK1/2, and JNK remains unchanged. It was further demonstrated that Rac1 activates both WAVE3 and p38 MAPK. Thus, WAVE3 is essential for Rac1-dependent activation of p38 MAPK pathway. Reports have indicated that WAVE3 regulates the MMP activity via p38 pathway (7). Overall, WAVE3 may play an important role in cancer cell invasion and metastasis through MMP production and p38 MAPK pathway. Furthermore, WAVE3 phosphorylation by Abl tyrosine kinase is important for MMPs activity.

WAVE3 and NFκB pathway

NFκB is a vital signaling pathway that is involved in pathogenesis as well as invasion and metastasis of several cancer types (91-93). Davuluri et al. (9) showed that there is a correlation between WAVE3 and NFκB signaling. They further highlighted the importance of WAVE3 for NFκB activation and demonstrated that knockdown of WAVE3 in MDA-MB 231 causes inhibition of NFκB activity and vice versa. Furthermore, the authors also showed that TNFα-induced stimulation of NFκB signaling activates Akt, and thereby causes cancer cells to undergo apoptosis and finally leads to cell death. In another study, it was revealed that either basic rich or PRD of WAVE3 is required for NFκB signaling (66). The authors showed that loss of WAVE3 in MDA-MB-231 cells causes inhibition of NFκB. This is because there is a nuclear translocation of NFκB. It appears that NFκB activates the production of MMPs, including MMP-1, MMP-3, and MMP-9. WAVE3-mediated modulation of NFκB, in addition to Akt signaling, is essential for formation of invadopodia as well as MMP9 expression. Additionally, phosphorylation of transcription factor p65 subunit and nuclear translocation are required for NFκB-mediated activation (9). Moreover, WAVE3 phosphorylation is important for the nuclear translocation as well as MMP-9 activation (27). Hence, WAVE3 plays a vital role in the regulation of NFκB signaling.

Cytoplasmic vs. nuclear function of WAVE3 and the role of WAVE3: YB1 interaction in the regulation of CSCs

Y-box-binding protein-1 (YB1), also known as Y-box transcription factor, is present in the cytoplasm as well as the nucleus of a cell (94,95). The role of YB1 is to regulate mRNA translation in the cytoplasm and regulate expression of CSC genes in the nucleus. YB1 expression is found to be elevated in various human cancers, especially aggressive breast cancer cell lines (96). A recent study has shown that WAVE3 binds to YB1 through its PRD and translocate YB1 to the nucleus, thereby activating CSC genes. It was also established that WAVE3 and YB1 work together to regulate the breast CSC population and gene expression. Therefore, a novel and never previously described function of WAVE3 in the nucleus, has been found to implicate WAVE3 in the regulation and maintenance of CSCs in breast cancer. Thus, WAVE3 may act as a potential biomarker for CSCs, and preventing WAVE3/YB1 binding may be a novel therapeutic target to treat TNBC (36).


Several signaling pathways have been shown to be associated with WAVE3 in the development, progression, and metastasis of several cancers, as well as the maintenance of CSCs in breast cancer (Figure 1). Therefore, targeting WAVE3 may serve as potential therapeutic strategy for treating cancer patients, including those with TNBC tumors. However, the domain of WAVE3 responsible for activating the signaling pathway has not been elucidated. Identifying the specificity of the different WAVE3 domains is crucial in the regulation of the different molecular signaling pathways and the modulation of the invasion-metastasis cascade.

Figure 1 Model representing the molecular signaling pathway of WAVE3 contributing to cancer progression and metastasis.


Funding: This work was supported by funding from the National Institute of Health (NIH) (Grant No. 7R01CA226921); and by startup funds from the MetroHealth System to KSA.


Provenance and Peer Review: This article was commissioned by the Guest Editor (Khalid Sossey-Alaoui) for the Series “Cancer Metastasis: Molecular signaling and therapeutic options” published in Annals of Translational Medicine. The article was sent for external peer review organized by the Guest Editor and the editorial office.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm.2020.02.16). The series “Cancer Metastasis: Molecular signaling and therapeutic options” was commissioned by the editorial office without any funding or sponsorship. KSA served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Annals of Translational Medicine from Sep 2019 to Aug 2021. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


  1. Takenawa T, Suetsugu S. The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 2007;8:37-48. [Crossref] [PubMed]
  2. Fernando HS, Davies SR, Chhabra A, et al. Expression of the WASP verprolin-homologues (WAVE members) in human breast cancer. Oncology 2007;73:376-83. [Crossref] [PubMed]
  3. Zhu Z, Chen W, Yin X, et al. WAVE3 induces EMT and promotes migration and invasion in intrahepatic cholangiocarcinoma. Dig Dis Sci 2016;61:1950-60. [Crossref] [PubMed]
  4. Sossey-Alaoui K, Li X, Cowell JK. c-Abl-mediated phosphorylation of WAVE3 is required for lamellipodia formation and cell migration. J Biol Chem 2007;282:26257-65. [Crossref] [PubMed]
  5. Sossey-Alaoui K, Safina A, Li X, et al. Down-regulation of WAVE3, a metastasis promoter gene, inhibits invasion and metastasis of breast cancer cells. Am J Pathol 2007;170:2112-21. [Crossref] [PubMed]
  6. Sossey-Alaoui K, Li X, Ranalli TA, et al. WAVE3-mediated cell migration and lamellipodia formation are regulated downstream of phosphatidylinositol 3-kinase. J Biol Chem 2005;280:21748-55. [Crossref] [PubMed]
  7. Sossey-Alaoui K, Ranalli TA, Li X, et al. WAVE3 promotes cell motility and invasion through the regulation of MMP-1, MMP-3, and MMP-9 expression. Exp Cell Res 2005;308:135-45. [Crossref] [PubMed]
  8. Sossey-Alaoui K, Downs-Kelly E, Das M, et al. WAVE3, an actin remodeling protein, is regulated by the metastasis suppressor microRNA, miR-31, during the invasion-metastasis cascade. Int J Cancer 2011;129:1331-43. [Crossref] [PubMed]
  9. Davuluri G, Augoff K, Schiemann WP, et al. WAVE3-NFκB interplay is essential for the survival and invasion of cancer cells. PLoS One 2014;9:e110627. [Crossref] [PubMed]
  10. Kang H, Wang J, Longley SJ, et al. Relative actin nucleation promotion efficiency by WASP and WAVE proteins in endothelial cells. Biochem Biophys Res Commun 2010;400:661-6. [Crossref] [PubMed]
  11. Kurisu S, Takenawa T. The WASP and WAVE family proteins. Genome Biol 2009;10:226. [Crossref] [PubMed]
  12. Pollitt AY, Insall RH. WASP and SCAR/WAVE proteins: the drivers of actin assembly. J Cell Sci 2009;122:2575-8. [Crossref] [PubMed]
  13. Takenawa T, Miki H. WASP and WAVE family proteins: key molecules for rapid rearrangement of cortical actin filaments and cell movement. J Cell Sci 2001;114:1801-9. [PubMed]
  14. Hall A. Rho GTPases and the actin cytoskeleton. Science 1998;279:509-14. [Crossref] [PubMed]
  15. Fernando HS, Sanders AJ, Kynaston HG, et al. WAVE3 is associated with invasiveness in prostate cancer cells. Urol Oncol 2010;28:320-7. [Crossref] [PubMed]
  16. Nozumi M, Nakagawa H, Miki H, et al. Differential localization of WAVE isoforms in filopodia and lamellipodia of the neuronal growth cone. J Cell Sci 2003;116:239-46. [Crossref] [PubMed]
  17. Eden S, Rohatgi R, Podtelejnikov AV, et al. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 2002;418:790-3. [Crossref] [PubMed]
  18. Gautreau A, Hsin-yi HH, Li J, et al. Purification and architecture of the ubiquitous Wave complex. Proc Natl Acad Sci 2004;101:4379-83. [Crossref] [PubMed]
  19. Innocenti M, Zucconi A, Disanza A, et al. Abi1 is essential for the formation and activation of a WAVE2 signalling complex. Nat Cell Biol 2004;6:319-27. [Crossref] [PubMed]
  20. Hume PJ, Humphreys D, Koronakis V. WAVE regulatory complex activation. Methods Enzymol 2014;540:363-79. [Crossref] [PubMed]
  21. Chen B, Brinkmann K, Chen Z, et al. The WAVE regulatory complex links diverse receptors to the actin cytoskeleton. Cell 2014;156:195-207. [Crossref] [PubMed]
  22. Koronakis V, Hume PJ, Humphreys D, et al. WAVE regulatory complex activation by cooperating GTPases Arf and Rac1. Proc Natl Acad Sci 2011;108:14449-54. [Crossref] [PubMed]
  23. Chen B, Chou HT, Brautigam CA, et al. Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. Elife 2017. [Crossref] [PubMed]
  24. Sasaki N, Miki H, Takenawa T. Arp2/3 complex-independent actin regulatory function of WAVE. Biochem Biophys Res Commun 2000;272:386-90. [Crossref] [PubMed]
  25. Kulkarni S, Augoff K, Rivera L, et al. Increased expression levels of WAVE3 are associated with the progression and metastasis of triple negative breast cancer. PloS One 2012;7:e42895. [Crossref] [PubMed]
  26. Sossey-Alaoui K. Surfing the big WAVE: Insights into the role of WAVE3 as a driving force in cancer progression and metastasis. Semin Cell Dev Biol 2013;24:287-97. [PubMed]
  27. Augoff K, McCue B, Plow EF, et al. WAVE3 modulates the invasion-metastasis cascade by regulating invadopodia structures, MMP activity and ECM degradation. AACR 2012:5315.
  28. Sossey-Alaoui K, Bialkowska K, Plow EF. The miR200 family of microRNAs regulates WAVE3-dependent cancer cell invasion. J Biol Chem 2009;284:33019-29. [Crossref] [PubMed]
  29. Ji Y, Li B, Zhu Z, et al. Overexpression of WAVE3 promotes tumor invasiveness and confers an unfavorable prognosis in human hepatocellular carcinoma. Biomed Pharmacother 2015;69:409-15. [Crossref] [PubMed]
  30. Huang S, Huang C, Chen W, et al. WAVE3 promotes proliferation, migration and invasion via the AKT pathway in pancreatic cancer. Int J Oncol 2018;53:672-84. [PubMed]
  31. Lu J, Wang SL, Wang YC, et al. High WAVE3 expression correlates with proliferation, migration and invasion in human ovarian cancer. Oncotarget 2017;8:41189-201. [Crossref] [PubMed]
  32. Taylor MA, Davuluri G, Parvani JG, et al. Upregulated WAVE3 expression is essential for TGF-β-mediated EMT and metastasis of triple-negative breast cancer cells. Breast Cancer Res Treat 2013;142:341-53. [Crossref] [PubMed]
  33. Davuluri G, Schiemann WP, Plow EF, et al. Loss of WAVE3 sensitizes triple-negative breast cancers to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis. JAKSTAT 2015;3:e1009276. [Crossref] [PubMed]
  34. Barbara M, Tsen A, Tenner L, et al. Talking genes in breast and pancreatic malignancies. Mater Sociomed 2019;31:146-9. [Crossref] [PubMed]
  35. Huang M, Zhang J, Yan C, et al. Small molecule HDAC inhibitors: promising agents for breast cancer treatment. Bioorganic Chem 2019;103184.
  36. Bledzka K, Schiemann B, Schiemann WP, et al. The WAVE3-YB1 interaction regulates cancer stem cells activity in breast cancer. Oncotarget 2017;8:104072. [Crossref] [PubMed]
  37. Glackin CA. Nanoparticle delivery of TWIST small interfering RNA and anticancer drugs: a therapeutic approach for combating cancer. Enzymes 2018;44:83-101. [Crossref] [PubMed]
  38. Hurvitz S, Mead M. Triple-negative breast cancer: advancements in characterization and treatment approach. Curr Opin Obstet Gynecol 2016;28:59-69. [PubMed]
  39. Kanaan YM, Sampey BP, Beyene D, et al. Metabolic profile of triple-negative breast cancer in African-American women reveals potential biomarkers of aggressive disease. Cancer Genomics-Proteomics 2014;11:279-94. [PubMed]
  40. Amirikia KC, Mills P, Bush J, et al. Higher population-based incidence rates of triple-negative breast cancer among young African-American women: implications for breast cancer screening recommendations. Cancer 2011;117:2747-53. [Crossref] [PubMed]
  41. Cunningham JE, Butler WM. Racial disparities in female breast cancer in South Carolina: clinical evidence for a biological basis. Breast Cancer Res Treat 2004;88:161-76. [Crossref] [PubMed]
  42. Sakthivel KM, Prabhu VV, Guruvayoorappan C. WAVEs: a novel and promising weapon in the cancer therapy tool box. Asian Pac J Cancer Prev 2012;13:1719-22. [Crossref] [PubMed]
  43. Donnelly SK, Cabrera R, Mao SP, et al. Rac3 regulates breast cancer invasion and metastasis by controlling adhesion and matrix degradation. J Cell Biol 2017;216:4331-49. [Crossref] [PubMed]
  44. Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncog 2013;18:43-73. [Crossref] [PubMed]
  45. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science 2011;331:1559-64. [Crossref] [PubMed]
  46. Guan X. Cancer metastases: challenges and opportunities. Acta Pharm Sin B 2015;5:402-18. [Crossref] [PubMed]
  47. Carey L, Winer E, Viale G, et al. Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol 2010;7:683-92. [Crossref] [PubMed]
  48. Carey LA. Directed therapy of subtypes of triple-negative breast cancer. Oncologist 2011;16 Suppl 1:71-8. [Crossref] [PubMed]
  49. Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer 2009;9:S73-81. [Crossref] [PubMed]
  50. Schneider BP, Winer EP, Foulkes WD, et al. Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res 2008;14:8010-8. [Crossref] [PubMed]
  51. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med 2010;363:1938-48. [Crossref] [PubMed]
  52. Finnegan TJ, Carey LA. Gene-expression analysis and the basal-like breast cancer subtype. Future Oncol 2007;3:55-63. [Crossref] [PubMed]
  53. Chang JC. Cancer stem cells: role in tumor growth, recurrence, metastasis, and treatment resistance. Medicine (Baltimore) 2016;95:S20-5. [Crossref] [PubMed]
  54. Ayob AZ, Ramasamy TS. Cancer stem cells as key drivers of tumour progression. J Biomed Sci 2018;25:20. [Crossref] [PubMed]
  55. Saeg F, Anbalagan M. Breast cancer stem cells and the challenges of eradication: a review of novel therapies. Stem Cell Investig 2018;5:39. [Crossref] [PubMed]
  56. Liu S, Wicha MS. Targeting breast cancer stem cells. J Clin Oncol 2010;28:4006-12. [Crossref] [PubMed]
  57. Schenone M, Dančík V, Wagner BK, et al. Target identification and mechanism of action in chemical biology and drug discovery. Nat Chem Biol 2013;9:232-40. [Crossref] [PubMed]
  58. Moazzam M, Ye L, Sun PH, et al. Knockdown of WAVE3 impairs HGF induced migration and invasion of prostate cancer cells. Cancer Cell Int 2015;15:51. [Crossref] [PubMed]
  59. Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 2006;6:259-69. [Crossref] [PubMed]
  60. Augoff K, McCue B, Plow EF, et al. miR-31 and its host gene lncRNA LOC554202 are regulated by promoter hypermethylation in triple-negative breast cancer. Mol Cancer 2012;11:5. [Crossref] [PubMed]
  61. Kawaguchi T, Yan L, Qi Q, et al. Overexpression of suppressive microRNAs, miR-30a and miR-200c are associated with improved survival of breast cancer patients. Sci Rep 2017;7:15945. [Crossref] [PubMed]
  62. Nabeshima K, Inoue T, Shimao Y, et al. Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int 2002;52:255-64. [Crossref] [PubMed]
  63. Lappas M, Riley C, Lim R, et al. MAPK and AP-1 proteins are increased in term pre-labour fetal membranes overlying the cervix: regulation of enzymes involved in the degradation of fetal membranes. Placenta 2011;32:1016-25. [Crossref] [PubMed]
  64. Yoon SO, Park SJ, Yun CH, et al. Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J Biochem Mol Biol 2003;36:128-37. [PubMed]
  65. Stamenkovic I. Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol 2003;200:448-64. [Crossref] [PubMed]
  66. Davuluri G, Sossey-Alaoui K, Plow E. WAVE3 regulates NFκB signaling and sensitizes cancer cells to apoptosis and cell death driven by TNFα. AACR 2013:2702.
  67. Sirvent A, Benistant C, Roche S. Cytoplasmic signalling by the c-Abl tyrosine kinase in normal and cancer cells. Biol Cell 2008;100:617-31. [Crossref] [PubMed]
  68. Jiménez C, Portela RA, Mellado M, et al. Role of the PI3K regulatory subunit in the control of actin organization and cell migration. J Cell Biol 2000;151:249-62. [Crossref] [PubMed]
  69. Qian Y, Corum L, Meng Q, et al. PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration. Am J Physiol-Cell Physiol 2004;286:C153-63. [Crossref] [PubMed]
  70. Yang J, Nie J, Ma X, et al. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer 2019;18:26. [Crossref] [PubMed]
  71. Serra V, Scaltriti M, Prudkin L, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 2011;30:2547-57. [Crossref] [PubMed]
  72. Costa RL, Han HS, Gradishar WJ. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat 2018;169:397-406. [Crossref] [PubMed]
  73. Massihnia D, Galvano A, Fanale D, et al. Triple negative breast cancer: shedding light onto the role of pi3k/akt/mtor pathway. Oncotarget 2016;7:60712-22. [Crossref] [PubMed]
  74. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129:1261-74. [Crossref] [PubMed]
  75. Meng Q, Xia C, Fang J, et al. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal 2006;18:2262-71. [Crossref] [PubMed]
  76. Yamaguchi H, Yoshida S, Muroi E, et al. Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation. J Cell Biol 2011;193:1275-88. [Crossref] [PubMed]
  77. Vasudevan KM, Barbie DA, Davies MA, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009;16:21-32. [Crossref] [PubMed]
  78. Jones E, Pu H, Kyprianou N. Targeting TGF-β in prostate cancer: therapeutic possibilities during tumor progression. Expert Opin Ther Targets 2009;13:227-34. [Crossref] [PubMed]
  79. Lebrun JJ. The dual role of TGFβ in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol 2012;2012:381428. [PubMed]
  80. Padua D, Massagué J. Roles of TGFbeta in metastasis. Cell Res 2009;19:89-102. [Crossref] [PubMed]
  81. Pickup M, Novitskiy S, Moses HL. The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer 2013;13:788-99. [Crossref] [PubMed]
  82. Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 2010;10:415-24. [Crossref] [PubMed]
  83. Sun N, Taguchi A, Hanash S. Switching roles of TGF-β in cancer development: implications for therapeutic target and biomarker studies. J Clin Med 2016;5:109. [Crossref] [PubMed]
  84. Neuzillet C, Tijeras-Raballand A, Cohen R, et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther 2015;147:22-31. [Crossref] [PubMed]
  85. Chang CJ, Chao CH, Xia W, et al. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 2011;13:317-23. [Crossref] [PubMed]
  86. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577-84. [Crossref] [PubMed]
  87. del Barco Barrantes I, Nebreda AR. Roles of p38 MAPKs in invasion and metastasis. Biochem Soc Trans 2012;40:79-84. [Crossref] [PubMed]
  88. Limoge M, Safina A, Truskinovsky AM, et al. Tumor p38MAPK signaling enhances breast carcinoma vascularization and growth by promoting expression and deposition of pro-tumorigenic factors. Oncotarget 2017;8:61969-81. [Crossref] [PubMed]
  89. Ono K, Han J. The p38 signal transduction pathway activation and function. Cell Signal 2000;12:1-13. [Crossref] [PubMed]
  90. Kim ES, Kim MS, Moon A. TGF-β-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 2004;25:1375-82. [PubMed]
  91. Yamamoto Y, Gaynor RB. Role of the NF-kB pathway in the pathogenesis of human disease states. Curr Mol Med 2001;1:287-96. [Crossref] [PubMed]
  92. Chaturvedi MM, Sung B, Yadav VR, et al. NF-κB addiction and its role in cancer: 'one size does not fit all'. Oncogene 2011;30:1615-30. [Crossref] [PubMed]
  93. Wu Y, Zhou BP. TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. Br J Cancer 2010;102:639-44. [Crossref] [PubMed]
  94. Eliseeva IA, Kim ER, Guryanov SG, et al. Y-box-binding protein 1 (YB-1) and its functions. Biochemistry (Mosc) 2011;76:1402-33. [Crossref] [PubMed]
  95. Matsumoto K, Kose S, Kuwahara I, et al. Y-box protein-associated acidic protein (YBAP1/C1QBP) affects the localization and cytoplasmic functions of YB-1. Sci Rep 2018;8:6198. [Crossref] [PubMed]
  96. Maurya PK, Mishra A, Yadav BS, et al. Role of Y Box Protein-1 in cancer: as potential biomarker and novel therapeutic target. J Cancer 2017;8:1900-7. [Crossref] [PubMed]
Cite this article as: Kansakar U, Wang W, Markovic V, Sossey-Alaoui K. Elucidating the molecular signaling pathways of WAVE3. Ann Transl Med 2020;8(14):900. doi: 10.21037/atm.2020.02.16