Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin-Deficient Cells
Bryony J Telford, Augustine Chen, Henry Beetham, James Frick, Tom P Brew, Cathryn M Gould, Andrew Single, Tanis Godwin, Kaylene J Simpson, Parry Guilford
MOLECULAR CANCER THERAPEUTICS | AMER ASSOC CANCER RESEARCH | Published : 2015
The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein-coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse famil..View full abstract
Awarded by New Zealand Health Research Council
This work was supported by the New Zealand Health Research Council (grant number 11/513 to P. Guilford) and the University of Otago (PhD Fellowships to B. Telford, H. Beetham, and A. Single). Additional funding support was received from No Stomach for Cancer Inc, the Degregario Family Foundation and the New Zealand Breast Cancer Research Partnership. The Victorian Centre for Functional Genomics (to K. Simpson) is funded by the Australian Cancer Research Foundation (ACRF), the Victorian Department of Industry, Innovation and Regional Development (DIIRD), the Australian Phenomics Network (APN) supported by funding from the Australian Government's Education Investment Fund through the Super Science Initiative, the Australasian Genomics Technologies Association (AMATA), the Brockhoff Foundation, and the Peter MacCallum Cancer Centre Foundation.