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

Hetal Patel, Rezvan Abduljabbar, Chun Fui Lai, Manikandan Periyasamy, Alison Harrod, Carolina Gemma, Jenny Steel, Naina Patel, Claudia Busonero, Dena Jerjees, Judit Remenyi, Sally Smith, Jennifer J Gomm, Luca Magnani, Balazs Gyorffy, J Louise Jones, Frances V Fuller-Pace, Sami Shousha, Laki Buluwela, Emad A RakhaIan O Ellis, R Charles Coombes, Simak Ali

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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-alpha(ERalpha).). Deregulation of cell cycle and transcriptional control is aare general featurefeatures of cancertumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics in cancer.

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 ERalpha expression and in particular with phosphorylation of ERalpha at serine 118, a site important for ERalpha transcriptional activity.

CONCLUSIONS: Expression of components of the CAK complex, CDK7, MAT1 and Cyclin H are elevated in breast cancer and correlates with ERalpha.. Like ERalpha, CDK7 expression is inversely proportional to poor prognostic factors and survival.

Original languageEnglish
Pages (from-to)5929-5938
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number23
Early online date14 Jun 2016
DOIs
Publication statusPublished - 1 Dec 2016

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    Patel, H., Abduljabbar, R., Lai, C. F., Periyasamy, M., Harrod, A., Gemma, C., Steel, J., Patel, N., Busonero, C., Jerjees, D., Remenyi, J., Smith, S., Gomm, J. J., Magnani, L., Gyorffy, B., Jones, J. L., Fuller-Pace, F. V., Shousha, S., Buluwela, L., ... 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