p21-activated kinases in ErbB2-positive breast cancer: A new therapeutic target?

The activation of receptor tyrosine kinases, particularly ErbB2, has been linked to the genesis and progression of breast cancer. Two of the central signaling pathways activated by ErbB2 are the Ras/Raf-1/Mek/Erk pathway, which plays an important role in tumor cell growth and migration, and the PI3K/Akt pathway, which plays an important role in cell survival. Recently, we and others have shown that signaling through the Ras-Erk pathway can be influenced by p21-activated kinase 1 (Pak1), an effector of the Rho family GTPases Rac and Cdc42. Expression of activated forms of Rac promotes activation of Erk through mechanisms involving Pak1 phosphorylation of Raf-1 and Mek1. In addition, Pak1 has also been implicated in the activation of Akt. However, our understanding regarding the degree to which Rho GTPases, and their effectors such as Pak1, contribute to ErbB2-mediated signaling is very limited. Recent results from our laboratory indicate that ErbB2 expression correlates with Pak activation in estrogen receptor negative human breast tumor samples. Using a three-dimensional (3D) culture of human MCF-10A mammary epithelial cells, we found that activation of Rac- Pak pathway by ErbB2 induces growth factor independent proliferation and promotes disruption of acini-like structures through the activation of the Erk and Akt pathways. We also observed that blocking Pak1 activity by small molecule inhibitors impeded the ability of activated ErbB2 to transform these cells and to activate its associated downstream signaling targets. In addition, we found that suppressing Pak activity in ErbB2 amplified breast cancer cells delayed tumor formation and downregulated Erk and Akt signaling in vivo. These results support a model in which Pak, by activating Erk and Akt, cooperates with ErbB2 in transforming mammary epithelial cells.