Abstract
Abstract p21-activated kinase-1 (Pak1) is frequently upregulated in human breast cancer and is required for transformation of mammary epithelial cells by ErbB2. However, its role in tumorigenesis in vivo, and the particular signaling pathways affected, are not defined. In this work, we examined the distinct roles of Pak1 and Pak2 in cellular and animal models of ErbB2-driven breast cancer. We found that inhibition of Pak1, but not Pak2, impedes transformation by ErbB2 in a 3D cell culture system, but that loss of either Pak1 or Pak2 causes loss of both Erk and Akt activation. A phospho-proteomic screen revealed that Pak1-deficient, but not Pak2-deficient, ErbB2 cells showed almost total loss of β-catenin expression that is accompanied by a significant reduction in almost all known β-catenin 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 the ability of ErbB2 to transform Pak1-deficient mammary epithelial cells. Lastly, we showed that small molecule inhibitors of Pak or β-catenin blocked transformation by ErbB2 in 3D culture and tumorigenesis by ErbB2 in mouse xenografts, and combined inhibition by both agents was synergistic. These findings establish Pak1 as a new target in ErbB2-driven breast cancer and define a new mechanism of action primarily through the β-catenin, but not the Erk or Akt, signaling pathways. Citation Format: Luis E. Arias-Romero, Olga Villamar-Cruz, Jonathan Chernoff. Pak1 and β-catenin inhibition blocks tumor progression in ErbB2-driven breast cancer models. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B31.
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