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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.

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-? (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. Clin Cancer Res; 22(23); 5929-38. ©2016 AACR.

SUBMITTER: Patel H

PROVIDER: S-EPMC5293170 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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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.

Patel Hetal H Abduljabbar Rezvan R Lai Chun-Fui CF Periyasamy Manikandan M Harrod Alison A Gemma Carolina C Steel Jennifer H JH Patel Naina N Busonero Claudia C Jerjees Dena D Remenyi Judit J Smith Sally S Gomm Jennifer J JJ Magnani Luca L Győrffy Balázs B Jones Louise J LJ Fuller-Pace Frances F Shousha Sami S Buluwela Laki L Rakha Emad A EA Ellis Ian O IO Coombes R Charles RC Ali Simak S

Clinical cancer research : an official journal of the American Association for Cancer Research 20160614 23

<h4>Purpose</h4>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-α (ER). Deregulation of cell cycle and transcriptional control are general features of tumor cells, highlighting the poten ...[more]

PMID: 27301701

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Project description:BackgroundThis study aimed to investigate whether an immunohistochemical prognostic model (IHC4 score) can predict the prognosis and the chemotherapy benefit in patients with estrogen receptor-positive (ER+)/human epidermal growth receptor 2-negative (HER2-) metastatic breast cancer (MBC).Materials and methodsWe developed a method to calculate the modified IHC4 (mIHC4) scores based on routine pathological reports and compared them with the original IHC4 scores that were much more difficult to calculate. Univariate and multivariate analyses were used to study the prognostic factors of progression-free survival (PFS) and overall survival (OS). The predictive value of mIHC4 score was also investigated.ResultsThe Sun Yat-sen Memorial Hospital data set included 315 patients with newly diagnosed ER+ MBC with a median follow-up of 25.6 months. Univariate and multivariate analysis showed that higher mIHC4 scores in metastatic lesions, but not the ones in primary tumors, were significantly associated with worse PFS and OS. The prognostic value of mIHC4 scores for PFS was validated using an independent Chinese Society of Clinical Oncology- Breast Cancer (CSCO-BC) data set. More importantly, subpopulation treatment effect pattern plot analysis showed that first-line endocrine therapy achieved better PFS and OS than chemotherapy in low-risk patients with ER+/HER2- MBC, whereas first-line chemotherapy was associated with improved PFS and OS compared with endocrine therapy in high-risk ones. The predictive value of mIHC4 score for PFS in selecting first-line endocrine therapy versus chemotherapy was also confirmed in the CSCO-BC data set.ConclusionmIHC4 scores in metastatic lesions are prognostic for the PFS and OS in patients with ER+ MBC. Low or high mIHC4 score may indicate the survival benefit in choosing first-line endocrine therapy or chemotherapy in patients with ER+/HER2- MBC, respectively.Implications for practiceThe modified IHC4 (mIHC4) score is easy to implement and able to predict patients with advanced and/or metastatic breast cancer. In addition, with the help of the mIHC4 score, physicians might be able to recommend chemotherapy or endocrine therapy as the first-line treatment for patients with high and low risk as predicted by the mIHC4 score.

Dataset Information

Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer.

Publications

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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