Abstract 2101: Role of CDK8 in estrogen receptor signaling in breast cancers

Abstract

Abstract The majority of breast cancers (BrCa) overexpress estrogen receptor (ER)α, which regulates transcription and drives estrogen-stimulated proliferation of ER+ tumor cells. ER+ patients usually receive adjuvant anti-estrogen therapy based on ER modification, downregulation, or estrogen depletion. Tumors frequently develop resistance to anti-estrogen therapy through various mechanisms, which may involve stimulation of ER itself or of downstream mediators of ER-driven transcription, as well as activation of alternative proliferation pathways, in particular those driven by HER2/EGFR. The treatment efficacy of hormone-resistant BrCa could be greatly augmented by targeting new druggable mediators of ER activity. We have now identified a transcription-regulating oncogenic kinase CDK8 as a potentiator of ER signaling and ER-driven BrCa cell proliferation. Immunohistochemical staining of breast tissue arrays and bioinformatics analysis of gene expression microarray data of breast cancer patients revealed that CDK8 is overexpressed in BrCa and that higher CDK8 expression correlates with the failure of systemic therapy. Among systemically untreated patients, higher CDK8 expression was correlated with shorter relapse-free survival in a subset of ER+ tumors that expressed the lowest levels of ERα. This correlation suggested that CDK8 could play a role in the progression of ER+ breast cancers with reduced levels of ER, possibly by stimulating the mitogenic effects of ER-mediated transcription. Indeed, a selective small-molecule CDK8 inhibitor (Senexin A) decreased estrogen-induced ER-dependent transcription and inhibited estrogen-stimulated proliferation of ER+ BrCa cell lines. Microarray analysis revealed that CDK8 inhibition diminished the induction of genes that show rapid and sustained activation by estrogen in ER+ cells. CDK8 inhibition had an additive effect in combination with anti-estrogens in ER+ BrCa and a synergistic effect with fulvestrant in BrCa cells resistant to estrogen deprivation. Some of these cell lines also express HER2/EGFR, and CDK8 inhibition in combination with a HER2/EGFR inhibitor lapatinib synergistically inhibited the growth of these cells. These results suggest that combining anti-estrogen and anti-CDK8 therapy may be more effective than conventional hormone therapy for ER+ BrCa. Citation Format: Martina McDermott, Balazs Gyorffy, Chang-uk Lim, Alexander Chumanevich, Zhengguan Yang, Mengqian Chen, James F. Catroppo, Igor Roninson, Eugenia V. Broude. Role of CDK8 in estrogen receptor signaling in breast cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2101. doi:10.1158/1538-7445.AM2014-2101