3667

p41-Arc is a regulatory component of mammalian Arp2/3 complex, an essential regulator of actin cytoskeleton and is required for the formation of branched networks of actin filaments at the cell cortex. Recent work from this laboratory has shown that p41-Arc is phosphorylated on threonine 21 by p21-activated kinase-1 (PAK1), a major growth factor-responsive signaling nodule in cancer cells. Mutation of threonine 21 to alanine in p41-Arc protein completely abolished the ability of Pak1 to phosphorylate p41-Arc and leads to a decreased migratory potential of breast cancer cells. Although p41-Arc phosphorylation and cell motility have been shown to be regulated by Pak1, the role of p41-Arc in breast cancer tumorigenesis remains unknown. Here we found that ectopic expression of p41-Arc in the human breast cancer cells stimulates the ability of cells to grow in an anchorage-independent manner and form tumors in nude mice. Interestingly, substitution of threonine 21 to alanine in p41-Arc blocked the tumor-forming ability of p41-Arc deregulation, implying an essential role of p41-Arc modification by Pak1 signaling. In addition, deregulation of p41-Arc resulted in an impaired cell proliferation; aberrant mitotic abnormalities, centrosome amplification and formation of anaphase bridges, and all these phenotypic changes were dependent on Pak1-activation of p41-Arc. Since mitotic and centrosomal defects are intimately linked with tumor development, we investigated the expression of p41-Arp in human breast tumors. We found an increased expression of p41-Arc mRNA as well as p41-Arc in breast tumors relative to the adjacent normal tissues from the same patients. These finding suggest that p41-Arp play a significant role in the maintenance of genomic integrity of mammalian cells and that an imbalance in the levels of p41-Arp could lead to chromosomal instability and transformation. (This study was supported by grants CA90970 and CA80066 from the National Institutes of Health to R.K.).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]