Upregulated WDR26 serves as a scaffold to coordinate PI3K/ AKT pathway-driven breast cancer cell growth, migration, and invasion

Yuanchao Ye; Xiaoyun Tang; Zhizeng Sun; Songhai Chen

doi:10.18632/oncotarget.7439

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Upregulated WDR26 serves as a scaffold to coordinate PI3K/ AKT pathway-driven breast cancer cell growth, migration, and invasion

Journal article

Open access

Peer reviewed

Upregulated WDR26 serves as a scaffold to coordinate PI3K/ AKT pathway-driven breast cancer cell growth, migration, and invasion

Yuanchao Ye, Xiaoyun Tang, Zhizeng Sun and Songhai Chen

Oncotarget, Vol.7(14), pp.17854-17869

04/05/2016

DOI: 10.18632/oncotarget.7439

PMCID: PMC4951255

PMID: 26895380

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Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway transmits signals downstream of receptor tyrosine kinases and G protein-coupled receptors (GPCRs), and is one of the most dysregulated pathways in breast cancer. PI3Ks and AKTs consist of multiple isoforms that play distinct and even opposite roles in breast cancer cell growth and metastasis. However, it remains unknown how the activities of various PI3K and AKT isoforms are coordinated during breast cancer progression. Previously, we showed WDR26 is a novel WD40 protein that binds Gβγ and promotes Gβγ signaling. Here, we demonstrate that WDR26 is overexpressed in highly malignant breast tumor cell lines and human breast cancer samples, and that WDR26 overexpression correlates with shortened survival of breast cancer patients. In highly malignant cell lines (MDA-MB231, DU4475 and BT549), downregulation of WDR26 expression selectively alleviated GPCR- but not EGF receptor-stimulated PI3K/AKT signaling and tumor cell growth, migration and invasion. In contrast, in a less malignant cell line (MCF7), WDR26 overexpression had the opposite effect. Additional studies indicate that downstream of GPCR stimulation, WDR26 serves as a scaffold that fosters assembly of a specific signaling complex consisting of Gβγ, PI3Kβ and AKT2. In an orthotopic xenograft mouse model of breast cancer, disrupting formation of this complex, by overexpressing WDR26 mutants in MDA-MB231 cells, abrogated PI3K/AKT activation and tumor cell growth and metastasis. Together, our results identify a novel mechanism regulating GPCR-dependent activation of the PI3K/AKT signaling axis in breast tumor cells, and pinpoint WDR26 as a potential therapeutic target for breast cancer.

Up-Regulation

Signal Transduction

Neoplasm Invasiveness

Humans

Cell Growth Processes - physiology

Mice, Transgenic

Cell Movement - physiology

Breast Neoplasms - metabolism

Breast Neoplasms - enzymology

Animals

Breast Neoplasms - genetics

Heterografts

Proteins - metabolism

MCF-7 Cells

Breast Neoplasms - pathology

Cell Line, Tumor

Female

Mice

Mice, Inbred BALB C

Proto-Oncogene Proteins c-akt - metabolism

Phosphatidylinositol 3-Kinase - metabolism

Details

Title: Subtitle: Upregulated WDR26 serves as a scaffold to coordinate PI3K/ AKT pathway-driven breast cancer cell growth, migration, and invasion
Creators: Yuanchao Ye - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Xiaoyun Tang - Current address: Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
Zhizeng Sun - Current address: Department of Pharmacology, Baylor College of Medicine, Houston, TX, USA
Songhai Chen - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Oncotarget, Vol.7(14), pp.17854-17869
DOI: 10.18632/oncotarget.7439
PMID: 26895380
PMCID: PMC4951255
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: United States
Grant note: R01 GM094255 / NIGMS NIH HHS GM094255 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 04/05/2016
Academic Unit: Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040002802771

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