Animals; Antineoplastic Agents (pharmacology); Blotting, Western; Breast Neoplasms (metabolism, pathology); Cell Line, Tumor; Chromatin Immunoprecipitation; Cyclin-Dependent Kinase 8 (antagonists & inhibitors); Drug Resistance, Neoplasm (drug effects); Estradiol (analogs & derivatives, pharmacology); Estrogen Receptor alpha (metabolism); Estrogens (biosynthesis); Female; Fulvestrant; Humans; Mice; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Protein Kinase Inhibitors (pharmacology); Transcription, Genetic; Transcriptome; Xenograft Model Antitumor Assays
Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers. However, many cancers develop resistance to hormone therapy while retaining ER expression. Identifying new druggable mediators of ER function can help to increase the efficacy of ER-targeting drugs. Cyclin-dependent kinase 8 (CDK8) is a Mediator complex-associated transcriptional regulator with oncogenic activities. Expression of CDK8, its paralog CDK19 and their binding partner Cyclin C are negative prognostic markers in breast cancer. Meta-analysis of transcriptome databases revealed an inverse correlation between CDK8 and ERα expression, suggesting that CDK8 could be functionally associated with ER. We have found that CDK8 inhibition by CDK8/19-selective small-molecule kinase inhibitors, by shRNA knockdown or by CRISPR/CAS9 knockout suppresses estrogen-induced transcription in ER-positive breast cancer cells; this effect was exerted downstream of ER. Estrogen addition stimulated the binding of CDK8 to the ER-responsive GREB1 gene promoter and CDK8/19 inhibition reduced estrogen-stimulated association of an elongation-competent phosphorylated form of RNA Polymerase II with GREB1. CDK8/19 inhibitors abrogated the mitogenic effect of estrogen on ER-positive cells and potentiated the growth-inhibitory effects of ER antagonist fulvestrant. Treatment of estrogen-deprived ER-positive breast cancer cells with CDK8/19 inhibitors strongly impeded the development of estrogen independence. In vivo treatment with a CDK8/19 inhibitor Senexin B suppressed tumor growth and augmented the effects of fulvestrant in ER-positive breast cancer xenografts. These results identify CDK8 as a novel downstream mediator of ER and suggest the utility of CDK8 inhibitors for ER-positive breast cancer therapy.
Digital Object Identifier (DOI)
Published in Oncotarget, Volume 8, Issue 8, 2017, pages 12558-12575.
Published under a Creative Commons Attribution 3.0 License.
McDermott, M., Chumanevich, A., Lim, C., Liang, J., Chen, M., & Altilia, S. et al. (2017). Inhibition of CDK8 mediator kinase suppresses estrogen dependent transcription and the growth of estrogen receptor positive breast cancer. Oncotarget, 8(8), 12558-12575. https://doi.org/10.18632/oncotarget.14894