Abstract 4004: P21-activated kinases (PAKs) are novel therapeutic targets in human breast cancer

Abstract

Abstract P21-activated kinases (PAKs) are important mediators of Rac and Cdc42 GTPase function as well as pathways required for Ras-driven tumorigenesis. PAKs have been implicated in signaling by growth factor receptors and morphogenetic processes that control cell polarity, invasion and actin cytoskeleton organization. To better understand the role of PAK1 and PAK4 in breast tumorigenesis, genomic copy number, mRNA and protein expression were determined for a panel of 291 human breast adenocarcinomas and loss-of function was assessed in cell lines using genetic and pharmacologic approaches. Interestingly, PAK1 genomic amplification at 11q13 was prevalent in luminal breast cancer and PAK1 levels in early ductal carcinoma in situ (DCIS) samples was similar to that of primary adenocarcinoma suggesting that PAK1 dysregulation could be an early event in some breast cancers. PAK1 protein expression in adenocarcinoma was associated with lymph node invasion and further increased expression was observed in metastatic tumors. In addition, primary and secondary (28 local recurrences, 56 metastases) adenocarcinomas from a total of 86 patients (81 with matching samples) were evaluated for PAK1 and PAK4 expression to determine modulation of these kinases following adjuvant hormone therapy. Breast cancer cell lines with PAK1 genomic amplification rapidly underwent caspase activation and apoptosis following inhibition of this kinase. Together, our results provide evidence for dysregulation of PAK1 in breast cancer and a role for PAK1 in cellular survival and proliferation in this indication. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4004. doi:1538-7445.AM2012-4004