Abstract
Cyclin‐dependent kinase 5 (Cdk5) is an atypical member of the cyclin‐dependent kinase family and functions as a serine/threonine kinase that can be activated by non‐cyclin binding activators p35 or p39. Cdk5 expression and activity has been linked with the development and progression of cancer; however, its expression in breast cancer has not been fully described. Protein expression of Cdk5 was determined in a large cohort of early‐stage invasive breast cancer tumours (n = 1110) with long‐term follow‐up data using immunohistochemistry. Expression of CDK5 mRNA was assessed in the METABRIC cohort (n = 1980). Low nuclear and cytoplasmic expression of Cdk5 expression was significantly associated with shorter breast cancer‐specific survival (P = .004 and P = .001, respectively). Importantly, low nuclear and cytoplasmic expression of Cdk5 remained associated with survival in multivariate analysis, including potentially confounding factors (hazard ratio (HR) = 0.612, 95% confidence interval (CI) = 0.418‐0.896, P = .011 and HR = 0.507, 95% CI = 0.318‐0.809, P = .004, respectively). In addition, low nuclear and cytoplasmic expression of Cdk5 was significantly associated with clinicopathological criteria associated with adverse patient prognosis. Low CDK5 mRNA expression was associated with shorter patient survival (P = .005) in the METABRIC cohort; no associations between copy gain or loss and survival were observed. These data suggest that low Cdk5 expression is associated with poor clinical outcome of breast cancer patients and may be of clinical relevance.
Highlights
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase and an atypical member of the cyclin-dependent kinase family
We demonstrate that, in a large cohort of breast cancer patients, low nuclear and cytoplasmic expression of Cdk[5] is significantly associated with adverse disease-specific survival (P = .004 and P = .001, respectively)
In addition to protein expression, low CDK5 mRNA expression was associated with shorter patient survival in the METABRIC cohort (P = .005)
Summary
| 6264 it is clear that Cdk[5] can play a role in cell types other than neurons and in the pathogenesis of certain diseases, such as cancer and Alzheimer's disease. Cdk[5] functions in numerous important cellular pathways; for example, phosphorylation of apurinic/apyrimidinic endonuclease 1 (Ape1) by Cdk5/p35 complexes reduces the AP endonuclease activity of Ape[1], an enzyme critical in the base excision repair pathway, to allow DNA damage to accumulate.[4] Cdk[5] phosphorylates focal adhesion kinase (FAK) allowing regulation of a microtubule fork that results in neuronal migration.[5] In cancer, Cdk[5] participates in numerous pathways associated with tumour progression. High Cdk[5] protein and mRNA expression is associated with clinicopathological features associated with a poor prognosis or adverse survival in a number of tumour types. High CDK5 mRNA expression has been associated with survival, and protein expression is associated with numerous clinicopathological criteria associated with a poor prognosis.[9,10]. We sought to determine the frequency of Cdk[5] overexpression in a large cohort of early-stage invasive breast cancers to determine whether Cdk[5] expression was associated with poor patient survival and test associations with clinicopathological criteria
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