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PMID: 21482774 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 109 ·No. 8 ·2012-02-21 ·Pages 2730-5

Mendes-Pereira AM, Sims D, Dexter T, Fenwick K, Assiotis I, Kozarewa I, Mitsopoulos C, Hakas J, Zvelebil M, Lord CJ, Ashworth A

Abstract

Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B, RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment.

MeSH Terms
Breast Neoplasms/drug therapy,genetics Cell Line, Tumor Drug Resistance, Neoplasm/drug effects,genetics Drug Screening Assays, Antitumor Female Genes, Neoplasm/genetics Genetic Testing/methods Genome, Human/genetics Humans RNA Interference/drug effects Reproducibility of Results Signal Transduction/drug effects Tamoxifen/pharmacology
Chemicals
Tamoxifen
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Mendes-Pereira Ana M
Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom.
Sims David
Dexter Tim
Fenwick Kerry
Assiotis Ioannis
Kozarewa Iwanka
Mitsopoulos Costas
Hakas Jarle
Zvelebil Marketa
Lord Christopher J
Ashworth Alan
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1018872108
Published
2012-02-21
Epub
2011-00-11
Pages
2730-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3286962
Subset
IM
Grants
Breast Cancer Now · BREAST CANCER NOW RESEARCH CENTRE · United Kingdom
External Links
PubMed source DOI: 10.1073/pnas.1018872108 PMC Full Text View journal details
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