Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer.
OBJECTIVE
CDK-activating kinase (CAK) is required for the regulation of the cell cycle and is a trimeric complex consisting of cyclin-dependent kinase 7 (CDK7), Cyclin H, and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-α (ER). Deregulation of cell cycle and transcriptional control are general features of tumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics.


METHODS
mRNA and protein expression of CDK7 and its essential cofactors cyclin H and MAT1 were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of >900 breast cancers was used to determine the association with clinicopathologic features and patient outcome.


RESULTS
We show that expressions of CDK7, cyclin H, and MAT1 are all closely linked at the mRNA and protein level, and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumor grade and size, and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ER expression and in particular with phosphorylation of ER at serine 118, a site important for ER transcriptional activity.


CONCLUSIONS
Expressions of components of the CAK complex, CDK7, MAT1, and Cyclin H are elevated in breast cancer and correlate with ER. Like ER, CDK7 expression is inversely proportional to poor prognostic factors and survival. Clin Cancer Res; 22(23); 5929-38. ©2016 AACR.
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Hetal
H
Patel
Department of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
Rezvan
R
Abduljabbar
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Chun-Fui
CF
Lai
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Manikandan
M
Periyasamy
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Alison
A
Harrod
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Carolina
C
Gemma
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Jennifer H
JH
Steel
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Naina
N
Patel
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Claudia
C
Busonero
Department of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
Dena
D
Jerjees
Division of Cancer Research, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
Judit
J
Remenyi
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, United Kingdom.
Sally
S
Smith
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, United Kingdom.
Jennifer J
JJ
Gomm
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Luca
L
Magnani
MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.|2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Balázs
B
Győrffy
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, United Kingdom.
Louise J
LJ
Jones
Division of Cancer Research, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
Frances
F
Fuller-Pace
Department of Histopathology, Charing Cross Hospital, Imperial College London, United Kingdom.
Sami
S
Shousha
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Laki
L
Buluwela
Department of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
Emad A
EA
Rakha
Department of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
Ian O
IO
Ellis
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
R Charles
RC
Coombes
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom. simak.ali@imperial.ac.uk.
Simak
S
Ali
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D056748:Cyclin H / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D010766:Phosphorylation / Q000235:genetics; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000235:genetics; D000095043:Cyclin-Dependent Kinase-Activating Kinase
C534751:CCNH protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056748:Cyclin H; C514215:MNAT1 protein, human; D011960:Receptors, Estrogen; D014157:Transcription Factors; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human