Pak1 kinase links ErbB2 to β-catenin in transformation of breast epithelial cells.

p21-Activated kinase-1 (Pak1) is frequently upregulated in human breast cancer and is required for transformation of mammary epithelial cells by ErbB2. Here, we show that loss of Pak1, but not the closely related Pak2, leads to diminished expression of β-catenin and its target genes. In MMTV-ErbB2 transgenic mice, loss of Pak1 prolonged survival, and mammary tissues of such mice showed loss of β-catenin. Expression of a β-catenin mutant bearing a phospho-mimetic mutation at Ser 675, a specific Pak1 phosphorylation site, restored transformation to ErbB2-positive, Pak1-deficient mammary epithelial cells. Mice bearing xenografts of ErbB2-positive breast cancer cells showed tumor regression when treated with small-molecule inhibitors of Pak or β-catenin, and combined inhibition by both agents was synergistic. These data delineate a signaling pathway from ErbB2 to Pak to β-catenin that is required for efficient transformation of mammary epithelial cells, and suggest new therapeutic strategies in ErbB2-positive breast cancer.