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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Cyclin H
Cyclin-Dependent Kinases
Estrogen Receptors
Estrogen Receptor alpha
Breast Neoplasms
Phosphotransferases
Neoplasms
Messenger RNA
RNA Polymerase II
Cell Cycle Checkpoints
Serine
Cell Cycle
Proteins
Breast
Transcription Factors

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Patel, Hetal ; Abduljabbar, Rezvan ; Lai, Chun Fui ; Periyasamy, Manikandan ; Harrod, Alison ; Gemma, Carolina ; Steel, Jenny ; Patel, Naina ; Busonero, Claudia ; Jerjees, Dena ; Remenyi, Judit ; Smith, Sally ; Gomm, Jennifer J ; Magnani, Luca ; Gyorffy, Balazs ; Jones, J Louise ; Fuller-Pace, Frances V ; Shousha, Sami ; Buluwela, Laki ; Rakha, Emad A ; Ellis, Ian O ; Coombes, R Charles ; Ali, Simak. / Expression of CDK7, cyclin H and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor- positive breast cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 23. pp. 5929-5938.
@article{05530b15cd564ac1a6b41cf92f56c743,
title = "Expression of CDK7, cyclin H and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor- positive breast cancer",
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.",
author = "Hetal Patel and Rezvan Abduljabbar and Lai, {Chun Fui} and Manikandan Periyasamy and Alison Harrod and Carolina Gemma and Jenny Steel and Naina Patel and Claudia Busonero and Dena Jerjees and Judit Remenyi and Sally Smith and Gomm, {Jennifer J} and Luca Magnani and Balazs Gyorffy and Jones, {J Louise} and Fuller-Pace, {Frances V} and Sami Shousha and Laki Buluwela and Rakha, {Emad A} and Ellis, {Ian O} and Coombes, {R Charles} and Simak Ali",
note = "This work was made possible by funding from Cancer Research UK and Breast Cancer Now. Some of the samples used in this study were obtained from the Breast Cancer Now Tissue Bank. We are also grateful for support from the NIHR Biomedical Research Centre funding scheme and the CRUK and Department of Health Imperial College Experimental Cancer Medicine Centre (ECMC).",
year = "2016",
month = "12",
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doi = "10.1158/1078-0432.CCR-15-1104",
language = "English",
volume = "22",
pages = "5929--5938",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research",
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Patel, H, Abduljabbar, R, Lai, CF, Periyasamy, M, Harrod, A, Gemma, C, Steel, J, Patel, N, Busonero, C, Jerjees, D, Remenyi, J, Smith, S, Gomm, JJ, Magnani, L, Gyorffy, B, Jones, JL, Fuller-Pace, FV, Shousha, S, Buluwela, L, Rakha, EA, Ellis, IO, Coombes, RC & 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, vol. 22, no. 23, pp. 5929-5938. https://doi.org/10.1158/1078-0432.CCR-15-1104

Expression of CDK7, cyclin H and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor- positive breast cancer. / Patel, Hetal; Abduljabbar, Rezvan; Lai, Chun Fui; Periyasamy, Manikandan; Harrod, Alison; Gemma, Carolina; Steel, Jenny; Patel, Naina; Busonero, Claudia; Jerjees, Dena; Remenyi, Judit; Smith, Sally; Gomm, Jennifer J; Magnani, Luca; Gyorffy, Balazs; Jones, J Louise; Fuller-Pace, Frances V; Shousha, Sami; Buluwela, Laki; Rakha, Emad A; Ellis, Ian O; Coombes, R Charles; Ali, Simak (Lead / Corresponding author).

In: Clinical Cancer Research, Vol. 22, No. 23, 01.12.2016, p. 5929-5938.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Expression of CDK7, cyclin H and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor- positive breast cancer

AU - Patel, Hetal

AU - Abduljabbar, Rezvan

AU - Lai, Chun Fui

AU - Periyasamy, Manikandan

AU - Harrod, Alison

AU - Gemma, Carolina

AU - Steel, Jenny

AU - Patel, Naina

AU - Busonero, Claudia

AU - Jerjees, Dena

AU - Remenyi, Judit

AU - Smith, Sally

AU - Gomm, Jennifer J

AU - Magnani, Luca

AU - Gyorffy, Balazs

AU - Jones, J Louise

AU - Fuller-Pace, Frances V

AU - Shousha, Sami

AU - Buluwela, Laki

AU - Rakha, Emad A

AU - Ellis, Ian O

AU - Coombes, R Charles

AU - Ali, Simak

N1 - This work was made possible by funding from Cancer Research UK and Breast Cancer Now. Some of the samples used in this study were obtained from the Breast Cancer Now Tissue Bank. We are also grateful for support from the NIHR Biomedical Research Centre funding scheme and the CRUK and Department of Health Imperial College Experimental Cancer Medicine Centre (ECMC).

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-15-1104

DO - 10.1158/1078-0432.CCR-15-1104

M3 - Article

C2 - 27301701

VL - 22

SP - 5929

EP - 5938

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 23

ER -