Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer

Elizabeth Iorns; Nicholas C Turner; Richard Elliott; Nelofer Syed; Ornella Garrone; Milena Gasco; Andrew N J Tutt; Tim Crook; Christopher J Lord; Alan Ashworth

doi:10.1016/j.ccr.2008.01.001

Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer

Elizabeth Iorns, Nicholas C Turner, Richard Elliott, Nelofer Syed, Ornella Garrone, Milena Gasco, Andrew N J Tutt, Tim Crook, Christopher J Lord, Alan Ashworth

Research output: Contribution to journal › Article › peer-review

Abstract

Therapies that target estrogen signaling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. Here, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. We demonstrate that CDK10 is an important determinant of resistance to endocrine therapies and show that CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. Patients with ER alpha-positive tumors that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumors.

Original language	English
Pages (from-to)	91-104
Number of pages	14
Journal	Cancer Cell
Volume	13
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2008.01.001
Publication status	Published - Feb 2008

Keywords / Materials (for Non-textual outputs)

Antineoplastic Agents, Hormonal/pharmacology
Breast Neoplasms/drug therapy
Cell Line, Tumor
Cyclin-Dependent Kinases/metabolism
DNA-Binding Proteins/metabolism
Drug Resistance, Neoplasm/drug effects
Enzyme Activation/drug effects
Estrogen Receptor alpha/metabolism
Estrogens/deficiency
G1 Phase/drug effects
Gene Silencing/drug effects
Humans
Ligands
Mitogen-Activated Protein Kinase 1/metabolism
Proto-Oncogene Proteins c-raf/genetics
RNA, Small Interfering/metabolism
Repressor Proteins/metabolism
Reproducibility of Results
Signal Transduction/drug effects
Survival Analysis
Tamoxifen/pharmacology
Transcription Factors/metabolism
Transcription, Genetic/drug effects
Transfection

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10.1016/j.ccr.2008.01.001

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title = "Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer",

abstract = "Therapies that target estrogen signaling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. Here, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. We demonstrate that CDK10 is an important determinant of resistance to endocrine therapies and show that CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. Patients with ER alpha-positive tumors that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumors.",

keywords = "Antineoplastic Agents, Hormonal/pharmacology, Breast Neoplasms/drug therapy, Cell Line, Tumor, Cyclin-Dependent Kinases/metabolism, DNA-Binding Proteins/metabolism, Drug Resistance, Neoplasm/drug effects, Enzyme Activation/drug effects, Estrogen Receptor alpha/metabolism, Estrogens/deficiency, G1 Phase/drug effects, Gene Silencing/drug effects, Humans, Ligands, Mitogen-Activated Protein Kinase 1/metabolism, Proto-Oncogene Proteins c-raf/genetics, RNA, Small Interfering/metabolism, Repressor Proteins/metabolism, Reproducibility of Results, Signal Transduction/drug effects, Survival Analysis, Tamoxifen/pharmacology, Transcription Factors/metabolism, Transcription, Genetic/drug effects, Transfection",

author = "Elizabeth Iorns and Turner, \{Nicholas C\} and Richard Elliott and Nelofer Syed and Ornella Garrone and Milena Gasco and Tutt, \{Andrew N J\} and Tim Crook and Lord, \{Christopher J\} and Alan Ashworth",

year = "2008",

month = feb,

doi = "10.1016/j.ccr.2008.01.001",

language = "English",

volume = "13",

pages = "91--104",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

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T1 - Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer

AU - Iorns, Elizabeth

AU - Turner, Nicholas C

AU - Elliott, Richard

AU - Syed, Nelofer

AU - Garrone, Ornella

AU - Gasco, Milena

AU - Tutt, Andrew N J

AU - Crook, Tim

AU - Lord, Christopher J

AU - Ashworth, Alan

PY - 2008/2

Y1 - 2008/2

N2 - Therapies that target estrogen signaling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. Here, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. We demonstrate that CDK10 is an important determinant of resistance to endocrine therapies and show that CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. Patients with ER alpha-positive tumors that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumors.

AB - Therapies that target estrogen signaling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. Here, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. We demonstrate that CDK10 is an important determinant of resistance to endocrine therapies and show that CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. Patients with ER alpha-positive tumors that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumors.

KW - Antineoplastic Agents, Hormonal/pharmacology

KW - Breast Neoplasms/drug therapy

KW - Cell Line, Tumor

KW - Cyclin-Dependent Kinases/metabolism

KW - DNA-Binding Proteins/metabolism

KW - Drug Resistance, Neoplasm/drug effects

KW - Enzyme Activation/drug effects

KW - Estrogen Receptor alpha/metabolism

KW - Estrogens/deficiency

KW - G1 Phase/drug effects

KW - Gene Silencing/drug effects

KW - Humans

KW - Ligands

KW - Mitogen-Activated Protein Kinase 1/metabolism

KW - Proto-Oncogene Proteins c-raf/genetics

KW - RNA, Small Interfering/metabolism

KW - Repressor Proteins/metabolism

KW - Reproducibility of Results

KW - Signal Transduction/drug effects

KW - Survival Analysis

KW - Tamoxifen/pharmacology

KW - Transcription Factors/metabolism

KW - Transcription, Genetic/drug effects

KW - Transfection

U2 - 10.1016/j.ccr.2008.01.001

DO - 10.1016/j.ccr.2008.01.001

M3 - Article

C2 - 18242510

SN - 1535-6108

VL - 13

SP - 91

EP - 104

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer

Abstract

Keywords / Materials (for Non-textual outputs)

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