Abstract: The Wiskott–Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE) family are a group of molecules that form a key link between GTPases and the actin cytoskeleton.

The role of WASP/WAVE family proteins in the control of actin polymerization through activation of the actin-related protein 2/3 complex is critical in the formation of the actin-based membrane protrusions seen in cell migration and invasion. 

For this reason, the activity of the WASP/WAVE family in cancer cell invasion and migration has been of great interest in recent years. Many reports have highlighted the potential of targeting the WASP/WAVE family as a therapy for the prevention of cancer progression, in particular breast cancer.

This review focuses on the role of the WASP/WAVE family in breast cancer cell invasion and migration and how this relates to the molecular mechanisms of WASP/WAVE activity, their exact contributions to the stages of cancer progression, and how this can lead to the development of anticancer drugs that target the WASP/WAVE family and related pathways.


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Keywords: WASP, WAVE, breast cancer, migration, invasion

Introduction

In females, breast cancer is the most frequently diagnosed malignancy and one of the main causes of cancer death,1 with survival rates much lower in patients with metastatic cancer.2

Metastasis, the process whereby cancer cells travel to and colonize distant sites through the lymphatic system or bloodstream, can signal a poor prognosis in patients. The metastatic cascade involves many complex cellular interactions and pathways.

Invasion is the initial critical step in metastasis and describes changes in cell adhe­sion, degradation of the cell surroundings, and importantly, the motility acquired by the tumor cell that confers a migratory phenotype and allows the cell to travel through tissues.3

Briefly, the cellular processes that occur in a motile cell include polariza­tion and extensions of actin-based protrusions, such as thin, finger-like filopodia and broader, sheet-like lamellipodia, in the direction of migration (Figure 1A).

Adhesions between the actin cytoskeleton of a migrating cell and the extracellular matrix (ECM) or neighboring cells stabilize protrusions and form traction sites to allow the cell to move over them.4

Specialized actin-rich protrusions, such as invadopodia, can also be formed by cancer cells, allowing them to degrade the ECM and invade into the surroundings.5

Formation of the protrusions at the leading edges of the migrating cell is controlled by actin polymerization and regulators of the actin cytoskeleton.6,7 The Rho GTPase protein family members, Rho, Rac, and Cdc42 in particular, play a key role in coordinating the processes involved in cell migration and invasion through the control of actin dynamics.8

The Wiskott–Aldrich syndrome (WAS) protein (WASP) and WASP family verprolin-homologous protein (WAVE) family are a group of molecules that form a key link between GTPases and the actin cytoskeleton.9

The role of WASP/WAVE family proteins in the control of actin polymerization through activa­tion of the actin-related protein (Arp)2/3 complex is critical in the formation of the actin-based membrane protrusions seen in cell migration and invasion.10

For this reason, the activity of the WASP/WAVE family in cancer cell invasion and migration has been of great interest in recent years. This is the main focus of this review, with an emphasis on WASP/WAVE activity in breast cancer cell motility.

(To view a larger version of Figure 1, click here.)