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

Patel, H.; Abduljabbar, R.; Lai, C.-F.; Periyasamy, M.; Harrod, A.; Gemma, C.; Steel, J. H.; Patel, N.; Busonero, C.; Jerjees, D.; Remenyi, J.; Smith, S.; Gomm, J. J.; Magnani, L.; Gyorffy, B.; Jones, L. J.; Fuller-Pace, F.; Shousha, S.; Buluwela, L.; Rakha, E. A.; Ellis, I. O.; Coombes, R. C.; Ali, S.

Abstract

Purpose: 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-a (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 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.

Citation

Patel, H., Abduljabbar, R., Lai, C.-F., Periyasamy, M., Harrod, A., Gemma, C., Steel, J. H., Patel, N., Busonero, C., Jerjees, D., Remenyi, J., Smith, S., Gomm, J. J., Magnani, L., Gyorffy, B., Jones, L. J., Fuller-Pace, F., Shousha, S., Buluwela, L., Rakha, E. A., …Ali, S. (2016). Expression of CDK7, cyclin H, and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor-positive breast cancer. Clinical Cancer Research, 22(23), 5929-5938. https://doi.org/10.1158/1078-0432.ccr-15-1104

• Journal Article Type: Article
• Acceptance Date: May 23, 2016
• Online Publication Date: Jun 14, 2016
• Publication Date: Dec 1, 2016
• Deposit Date: Nov 21, 2018
• Journal: Clinical Cancer Research
• Print ISSN: 1078-0432
• Electronic ISSN: 1557-3265
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 22
• Issue: 23
• Pages: 5929-5938
• DOI: https://doi.org/10.1158/1078-0432.ccr-15-1104
• Public URL: https://nottingham-repository.worktribe.com/output/1293660
• Publisher URL: http://clincancerres.aacrjournals.org/content/22/23/5929