Coexpression of Arp2 and WAVE2 predicts poor outcome in invasive breast carcinoma

Abstract

Breast carcinoma with a high histologic grade is highly invasive and metastatic. One reason for its irregular morphology is the formation of excessive protrusions due to assemblages of branched actin filament networks. In mammalian cells, the actin-related protein 2 and 3 (Arp2/3) complex initiates actin assembly to form lamellipodial protrusions by binding to the Wiskott-Aldrich syndrome (WASP)/WASP family verprolinehomologous protein2 (WAVE2), a member of the WASP protein family. In this study, the localization Arp2 and WAVE2 in breast carcinoma was investigated to clarify whether coexpression of the two proteins is associated with histologic grade or patient outcome. Immunohistochemical staining of Arp2 and WAVE2 was performed on mirror specimens of 197 breast carcinomas, and the association between coexpression of the two proteins and clinicopathologic factors was examined. Kaplan-Meier disease-free survival and overall survival curves were analyzed to determine the prognostic significance of Arp2 and WAVE2 coexpression in breast carcinoma. Coexpression of Arp2 and WAVE2 was detected in 64 (36%) of 179 invasive ductal carcinomas and in 2 (11%) of 18 ductal carcinomas in situ, but was not detected in any adjacent non-cancerous tissue. The proportion of cancer cells expressing both Arp2 and WAVE2 was significantly higher in cases with high histologic grade (Po0.0001), and cases with lymph node metastasis (P ¼ 0.0150). The patients whose cancer cells showed such coexpression had shorter disease-free (P ¼ 0.0002) and overall survival (P ¼ 0.0122) than patients whose cancer cells expressed only one or none of Arp2 and WAVE2. Multivariate Cox regression analysis revealed that coexpression of Arp2 and WAVE2 is an independent factor for both tumor recurrence (P ¼ 0.0308) and death (P ¼ 0.0455). These results indicate that coexpression of Arp2 and WAVE2 is a significant prognostic factor that is closely associated with aggressive morphology of invasive ductal carcinoma of the breast.

EMT, the cytoskeleton, and cancer cell invasion

“…The activity of the Arp2/3 complex itself is controlled by actin nucleation-promoting factors, such as the N-WASP or the Scar/WAVE complexes which are themselves recruited to and activated at the membrane by Rac1 [172][173][174]. Increased expression of Arp2/3 and WAVE2 has been shown to correlate with poor prognosis in breast and liver carcinomas underlining the relevance of lamellipodia-like structures in cancer progression [175,176]. Furthermore, the formation of lamellipodia is also observed upon ErbB2-driven EMT in epithelial cells, indicating that the formation of lamellipodia-like structures underlies the increased invasiveness observed during EMT [177].…”

Bench to bedside and back again: Molecular mechanisms of α-catenin function and roles in tumorigenesis

“…For example, inhibition of the Arp2/3 complex by RNAi of one of its protein components led to less than 5% of cells with active lamellipodia [79], which demonstrates the importance of Arp2/3 in membrane activity. On the other hand, increased expression of Arp2/3 and its activator WASP in invasive breast cancer is prognostic for decreased survival and cancer recurrence [80]. Therefore, loss of α-catenin from the membrane of cancer cells could lead to increased Arp2/3 activity, membrane activity and cell migration.…”

Pseudopodial Actin Dynamics Control Epithelial-Mesenchymal Transition in Metastatic Cancer Cells

“…Actin cytoskeleton regulators were also recently identified as critical determinants of lymphoma progression in a loss-of-function RNA screen of mouse tumor models (6). Increased expression of Arp2/3 and WAVE2 correlates with poor prognosis in breast and liver carcinomas underlining the relevance of actin-dependent membrane protrusion and pseudopodia formation in cancer progression (7,8). Cytokine activation stimulates intracellular signaling pathways that regulate the local reorganization of the actin cytoskeleton at the leading edge and drive pseudopodial protrusion (9)(10)(11).…”