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Expression of CDK7, cyclin H and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor positive breast cancer

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Title: Expression of CDK7, cyclin H and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor positive breast cancer
Authors: Patel, H
Abduljabbar, R
Chun-Fui, L
Periyasamy, M
Harrod, A
Gemma, C
Steel, JH
Patel, N
Busonero, C
Jerjees, D
Remenyi, J
Smith, S
Gomm, JJ
Magnani, L
Győrffy, B
Jones, LJ
Fuller-Pace, F
Shousha, S
Buluwela, L
Rakha, EA
Ellis, IO
Coombes, RC
Ali, S
Item Type: Journal Article
Abstract: Purpose: CDK-activation 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. Experimental Design: mRNA and protein expression of CDK7 and its essential co-factors cyclinH 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 clinicopathological features and patient outcome. Results: We show that expression of CDK7, cyclinH 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 tumour 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: Expression of components of the CAK complex, CDK7, MAT1 and Cyclin H are elevated in breast cancer and correlates with ER. Like ERα , CDK7 expression is inversely proportional to poor prognostic factors and survival.
Issue Date: 14-Jun-2016
Date of Acceptance: 23-May-2016
URI: http://hdl.handle.net/10044/1/33430
DOI: https://dx.doi.org/10.1158/1078-0432.CCR-15-1104
ISSN: 1557-3265
Publisher: American Association for Cancer Research
Start Page: 5929
End Page: 5938
Journal / Book Title: Clinical Cancer Research
Volume: 22
Issue: 23
Copyright Statement: © 2016 American Association for Cancer Research.
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Cancer Research UK
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Cancer Research Technology Ltd
Funder's Grant Number: C37990/A12196
2011NovPR31
C37/A12011
RDEMC 79560
RDB01 79560
TEPO-4005156
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
TRANSCRIPTION FACTOR TFIIH
4/6 INHIBITOR PALBOCICLIB
CELL-CYCLE
BIOLOGICAL SIGNIFICANCE
BIOMARKER ASSESSMENT
ANDROGEN RECEPTOR
ACTIVATING KINASE
ER-ALPHA
PHOSPHORYLATION
BINDING
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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