Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer

Abstract

CDK8 and its paralog CDK19, in complex with CCNC, MED12 and MED13, are transcriptional regulators that mediate several carcinogenic pathways and the chemotherapy-induced tumor-supporting paracrine network. Following up on our previous observation that CDK8, CDK19 and CCNC RNA expression is associated with shorter relapse-free survival (RFS) in breast cancer, we now found by immunohistochemical analysis that CDK8/19 protein is overexpressed in invasive ductal carcinomas relative to non-malignant mammary tissues. Meta-analysis of transcriptomic data revealed that higher CDK8 expression is associated with shorter RFS in all molecular subtypes of breast cancer. These correlations were much stronger in patients who underwent systemic adjuvant therapy, suggesting that CDK8 impacts the failure of systemic therapy. The same associations were found for CDK19, CCNC and MED13. In contrast, MED12 showed the opposite association with a longer RFS. The expression levels of CDK8 in breast cancer samples were directly correlated with the expression of MYC, as well as CDK19, CCNC and MED13 but inversely correlated with MED12. CDK8, CDK19 and CCNC expression was strongly increased and MED12 expression was decreased in tumors with mutant p53. Gene amplification is the most frequent type of genetic alterations of CDK8, CDK19, CCNC and MED13 in breast cancers (9.7% of which have amplified MED13), whereas point mutations are more common in MED12. These results suggest that the expression of CDK8 and its interactive genes has a profound impact on the response to adjuvant therapy in breast cancer in accordance with the role of CDK8 in chemotherapy-induced tumor-supporting paracrine activities.

Fig. (1)

CDK8/19 protein expression and genetic alterations of CDK module components in breast cancers. A–F: representative images of CDK8/19 IHC staining in different types of mammary tissues. Left: H&E staining, 10 × objective. Center: CDK8/19 IHC (DAB) with methyl green counterstain, 10 × objective, Right: same as center, 40 × objective. A. Normal breast tissue; B. Epithelial hyperplasia; C. Lobular carcinoma; D–F. Infiltrating ductal carcinoma, not otherwise specified (3 different tumors); G: IHC scores for different types of mammary tissue samples. H: genetic alterations of CDK8, CDK19, CCNC, MED12 and MED13 in TCGA panel of 968 breast cancers; only cancers showing alteration in any of these genes are presented. Numbers indicate the combined frequency of all genetic alterations for each gene. Red: gene amplification. Blue: homozygous deletion. Green: point mutation.

Fig. (2)

Association of CDK8 expression with RFS in Affymetrix breast cancer microarray data determined using KM-plotter online survival analysis tool (http://kmplot.com/analysis/) with “Auto select best cutoff” option. The results are shown for all breast cancers and their molecular subtypes, including subsets that did not receive or received systemic therapy after sample collection. Note that the sums of the patient numbers in individual subtypes are less than the number of all patients, since the molecular subtype or the treatment status was not reported for every patient.

Fig. (3)

Association of CDK19, CCNC, MED12, MED13 and TOP2A expression with RFS in Affymetrix breast cancer microarray data, plotted for all patients and the subsets that did not receive or received systemic therapy.

Fig. (4)

Intergenic correlations of the expression of CDK8 and its interactive genes in Affymetrix breast cancer microarray data. (A) Pairwise correlations of expression levels for the indicated genes in 3,491 cancers: median expression plotted for 35 bins of 100 samples assembled into bins according to the levels of the first gene (X-axis); the second gene (median expression in the bin shown on the Y-axis) is labeled at the top of each graph. p-values are based on Spearman rank correlation. (B) Expression levels of the indicated genes in p53 wild-type and p53-mutant tumors in 319 patients with known p53 status. The columns represent the average gene expression; the error bars represent the 95% confidence interval. p-values are based on Mann-Whitney U-test.