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-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.

Cyclin H predicts the poor prognosis and promotes the proliferation of ovarian cancer

“…Here, we observed that cyclin H was positively correlated with the increased tumor grade of ovarian cancer and the expression of the proliferation markers Ki-67 and p-CDK2. Similar results are reported by diffuse large B-cell lymphoma [27], esophageal squamous cell carcinoma [12], and breast cancer [11]. Prashant Bavi et al's study concluded that a reduced or an absent cyclin H expression was signi cantly associated with the poor overall survival of patients with diffuse large B-cell lymphoma [27].…”

“…Cyclin H, a member of the cyclin family, together with CDK7 and MAT1 forms the CDK-activating kinase (CAK) trimeric complex, which is necessary for the regulation of cell cycle and proliferation. Abnormal expression of cyclin H is reported in a variety of tumors such as breast cancer [11], esophageal cancer [12], endometrial cancer [13], and gastrointestinal stromal tumors [14]. However, the clinical signi cance and the biological function of cyclin H in ovarian cancer remains unclear.…”

Inhibition of cyclin‐dependent kinase 7 down‐regulates yes‐associated protein expression in mesothelioma cells

“…32,33 CDK7 regulates transcription primarily by phosphorylating serine 5 at the C-terminal domain of RNA polymerase II, as well as transcription factors such as oestrogen receptor-α. 34,35 The manner in which CDK7…”

The essential and multifunctional TFIIH complex

“…Numerous cancers appear to be dependent on elevated CDK7 activity to drive their oncogenic state . Because of its role in cell cycle regulation, CDK7 activity cannot be entirely de‐coupled from its broad transcriptional effects.…”

“…Numerous cancers appear to be dependent on elevated CDK7 activity to drive their oncogenic state. 192,193 Because of its role in cell cycle regulation, CDK7 activity cannot be entirely de-coupled from its broad transcriptional effects. However, elevated expression of oncogenes is enabled by clusters of enhancers, or super-enhancers, [194][195][196] that require CDK7 activity to maintain their high-level expression.…”