Abstract 5000: Upregulation of WDR26 promotes breast cancer cell growth, migration and invasion via enhancing PI3K/AKT signaling

Abstract

Abstract Background: The phosphatidylinositol 3-kinase (PI3K) pathway is one of the most deregulated pathways in breast cancer. One of PI3K isoforms, p110 β, has been shown to be activated predominantly by G protein-coupled receptors (GPCRs) through the heterotrimeric G protein βγ subunits (Gβγ), and plays a key role in breast cancer development. PI3Ks mediates their effects primarily through the activation of select AKT, which consists of three isoforms. We have recently made important observations that diverse GPCRs converge at Gβγ to promote breast tumor cell growth and migration both in vitro and in vivo, and that a novel Gβγ-interacting protein, WDR26, promotes Gβγ-dependent signal transductions, including PI3K/AKT activation. In this study, we have evaluated the role of WDR26 in regulating PI3K/AKT signaling for breast tumor cell growth, migration and invasion. Methods: The level of WDR26 expression was evaluated in breast cancer cells and human breast cancer samples by Western blotting and immunohistochemistry analysis. WDR26 was then downregulated by siRNAs or overexpressed in breast cancer cells, and the effects on PI3K/AKT activation, tumor cell proliferation, migration and invasion were evaluated in vitro. Results: WDR26 was upregulated in a subset of highly malignant and invasive breast tumor cell lines (such as MDA-MB231 and DU4475), and high grade human breast tumor samples. Upon GPCR stimulation of breast tumor cells, WDR26 facilitated the formation of a signaling complex consisting of Gβγ, PI3Kβ and AKT2. Downregulation of WDR26 in MDA-MB231 and DU4475 cells using RNA interference inhibited PI3K/AKT activation, tumor cell growth, migration and invasion. Similar effects were achieved by disruption of WDR26 function through induced expression of WDR26 deletion mutants in MDA-MB231 cells. Conversely, overexpression of WDR26 in MCF7 cells enhanced PI3K/AKT activation and rendered MCF7 cell migration and enhanced proliferation. Conclusions: Together, these results indicate that WDR26 serves as a scaffold to foster interactions between Gβγ, PI3Kβ and AKT2, thereby promoting Gβγ-dependent PI3K/AKT activation, thereby regulating breast tumor progression. WDR26, thus, may represent a novel target for the intervention of breast tumors. Note: This abstract was not presented at the meeting. Citation Format: Yuanchao Ye, Songhai Chen. Upregulation of WDR26 promotes breast cancer cell growth, migration and invasion via enhancing PI3K/AKT signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5000. doi:10.1158/1538-7445.AM2014-5000