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
SN - 1078-0432
VL - 22
SP - 5929
EP - 5938
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -
