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Title: Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer
Authors: Tang Y.C. 
Ho S.-C. 
Tan E. 
Ng A.W.T. 
McPherson J.R. 
Goh G.Y.L.
Teh B.T. 
Bard F. 
Rozen S.G. 
Keywords: phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase
protein kinase LKB1
short hairpin RNA
small interfering RNA
NUAK1 protein, human
phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase
protein kinase
protein serine threonine kinase
PTEN protein, human
repressor protein
small interfering RNA
STK11 protein, human
tumor protein
ADAMTS20 gene
AP1M2 gene
breast cancer
breast cancer cell line
breast epithelium cell
cell viability
cohort analysis
controlled study
drug sensitivity
enzyme inhibition
functional genomics
gene activity
gene mutation
HMMR gene
human cell
NUAK1 gene
PIK3CB gene
RNA interference
STK11 gene
breast tumor
gene expression regulation
human genome
lethal mutation
mammary gland
tumor cell line
Breast Neoplasms
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Genome, Human
Mammary Glands, Human
Neoplasm Proteins
Protein Kinases
Protein-Serine-Threonine Kinases
PTEN Phosphohydrolase
Repressor Proteins
RNA, Small Interfering
Synthetic Lethal Mutations
Issue Date: 2018
Citation: Tang Y.C., Ho S.-C., Tan E., Ng A.W.T., McPherson J.R., Goh G.Y.L., Teh B.T., Bard F., Rozen S.G. (2018). Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer. Breast Cancer Research 20 (1) : 22. ScholarBank@NUS Repository.
Abstract: Background: Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressors in breast cancer. While PTEN itself is not considered a druggable target, PTEN synthetic-sick or synthetic-lethal (PTEN-SSL) genes are potential drug targets in PTEN-deficient breast cancers. Therefore, with the aim of identifying potential targets for precision breast cancer therapy, we sought to discover PTEN-SSL genes present in a broad spectrum of breast cancers. Methods: To discover broad-spectrum PTEN-SSL genes in breast cancer, we used a multi-step approach that started with (1) a genome-wide short interfering RNA (siRNA) screen of ~ 21,000 genes in a pair of isogenic human mammary epithelial cell lines, followed by (2) a short hairpin RNA (shRNA) screen of ~ 1200 genes focused on hits from the first screen in a panel of 11 breast cancer cell lines; we then determined reproducibility of hits by (3) identification of overlaps between our results and reanalyzed data from 3 independent gene-essentiality screens, and finally, for selected candidate PTEN-SSL genes we (4) confirmed PTEN-SSL activity using either drug sensitivity experiments in a panel of 19 cell lines or mutual exclusivity analysis of publicly available pan-cancer somatic mutation data. Results: The screens (steps 1 and 2) and the reproducibility analysis (step 3) identified six candidate broad-spectrum PTEN-SSL genes (PIK3CB, ADAMTS20, AP1M2, HMMR, STK11, and NUAK1). PIK3CB was previously identified as PTEN-SSL, while the other five genes represent novel PTEN-SSL candidates. Confirmation studies (step 4) provided additional evidence that NUAK1 and STK11 have PTEN-SSL patterns of activity. Consistent with PTEN-SSL status, inhibition of the NUAK1 protein kinase by the small molecule drug HTH-01-015 selectively impaired viability in multiple PTEN-deficient breast cancer cell lines, while mutations affecting STK11 and PTEN were largely mutually exclusive across large pan-cancer data sets. Conclusions: Six genes showed PTEN-SSL patterns of activity in a large proportion of PTEN-deficient breast cancer cell lines and are potential specific vulnerabilities in PTEN-deficient breast cancer. Furthermore, the NUAK1 PTEN-SSL vulnerability identified by RNA interference techniques can be recapitulated and exploited using the small molecule kinase inhibitor HTH-01-015. Thus, NUAK1 inhibition may be an effective strategy for precision treatment of PTEN-deficient breast tumors. © 2018 The Author(s).
Source Title: Breast Cancer Research
ISSN: 1465-5411
DOI: 10.1186/s13058-018-0949-3
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