Please use this identifier to cite or link to this item: https://doi.org/10.1186/bcr2354
Title: BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A
Authors: Puppe, J
Drost, R
Liu, X
Joosse, S.A
Evers, B
Cornelissen-Steijger, P
Nederlof, P
Yu, Q 
Jonkers, J
van Lohuizen, M
Pietersen, A.M
Keywords: 3 deazaneplanocin A
BRCA1 protein
transcription factor EZH2
3 deazaneplanocin
3-deazaneplanocin
adenosine
BRCA1 protein
BRCA1 protein, human
drug derivative
Ezh2 protein, mouse
histone lysine methyltransferase
hybrid protein
messenger RNA
RNA
small interfering RNA
animal cell
animal experiment
animal model
article
breast cancer
cancer cell culture
cancer inhibition
cell differentiation
controlled study
drug sensitivity
gene mutation
gene overexpression
gene repression
genetic analysis
heterozygote
human
human tissue
immunohistochemistry
mouse
nonhuman
phenotype
protein expression
animal
biosynthesis
breast tumor
DNA repair
drug antagonism
drug delivery system
drug effect
female
gene silencing
genetics
metabolism
mutation
pathology
physiology
tumor cell line
tumor suppressor gene
Adenosine
Animals
BRCA1 Protein
Breast Neoplasms
Cell Line, Tumor
DNA Repair
Drug Delivery Systems
Female
Gene Knockdown Techniques
Genes, BRCA1
Histone-Lysine N-Methyltransferase
Humans
Mice
Mutation
Recombinant Fusion Proteins
RNA, Messenger
RNA, Neoplasm
RNA, Small Interfering
Issue Date: 2009
Citation: Puppe, J, Drost, R, Liu, X, Joosse, S.A, Evers, B, Cornelissen-Steijger, P, Nederlof, P, Yu, Q, Jonkers, J, van Lohuizen, M, Pietersen, A.M (2009). BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A. Breast Cancer Research 11 (4) : R63. ScholarBank@NUS Repository. https://doi.org/10.1186/bcr2354
Rights: Attribution 4.0 International
Abstract: Introduction: Treatment of breast cancer is becoming more individualized with the recognition of tumor subgroups that respond differently to available therapies. Breast cancer 1 gene (BRCA1)-deficient tumors are usually of the basal subtype and associated with poor survival rates, highlighting the need for more effective therapy.Methods: We investigated a mouse model that closely mimics breast cancer arising in BRCA1-mutation carriers to better understand the molecular mechanism of tumor progression and tested whether targeting of the Polycomb-group protein EZH2 would be a putative therapy for BRCA1-deficient tumors.Results: Gene expression analysis demonstrated that EZH2 is overexpressed in BRCA1-deficient mouse mammary tumors. By immunohistochemistry we show that an increase in EZH2 protein levels is also evident in tumors from BRCA1-mutation carriers. EZH2 is responsible for repression of genes driving differentiation and could thus be involved in the undifferentiated phenotype of these tumors. Importantly, we show that BRCA1-deficient cancer cells are selectively dependent on their elevated EZH2 levels. In addition, a chemical inhibitor of EZH2, 3-deazaneplanocin A (DZNep), is about 20-fold more effective in killing BRCA1-deficient cells compared to BRCA1-proficient mammary tumor cells.Conclusions: We demonstrate by specific knock-down experiments that EZH2 overexpression is functionally relevant in BRCA1-deficient breast cancer cells. The effectiveness of a small molecule inhibitor indicates that EZH2 is a druggable target. The overexpression of EZH2 in all basal-like breast cancers warrants further investigation of the potential for targeting the genetic make-up of this particular breast cancer type. © 2009 Puppe et al.; licensee BioMed Central Ltd.
Source Title: Breast Cancer Research
URI: https://scholarbank.nus.edu.sg/handle/10635/183273
ISSN: 14655411
DOI: 10.1186/bcr2354
Rights: Attribution 4.0 International
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