Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer.
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.
Iorns
Elizabeth
E
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
Turner
Nicholas C
NC
Elliott
Richard
R
Syed
Nelofer
N
Garrone
Ornella
O
Gasco
Milena
M
Tutt
Andrew N J
AN
Crook
Tim
T
Lord
Christopher J
CJ
Ashworth
Alan
A
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000172:deficiency; D016193:G1 Phase / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; C107465:ERF protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors; D013629:Tamoxifen; D019908:Proto-Oncogene Proteins c-raf; C501013:CDK10 protein, human; D018844:Cyclin-Dependent Kinases; D019950:Mitogen-Activated Protein Kinase 1