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Updated: Jan 29, 2026

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
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CDK8 Inhibition Increases E2F1 Transcriptional Activity and Promotes STAT3-Dependent Suppression of Mcl-1 in

Sandra Do1, Shengxi Li1, Rui Xiong1

  • 1Department of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA.

International Journal of Molecular Sciences
|January 28, 2026
PubMed

Insights

Targeting cyclin-dependent kinase 8 (CDK8) with inhibitors shows promise for triple-negative breast cancer. CDK8 inhibition affects key proteins like E2F1 and STAT3, modulating apoptosis and offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclin-dependent kinase 8 (CDK8) is recognized as an oncogene product.
  • Targeting CDK8 is a developing strategy for cancer therapy.
  • Triple-negative breast cancer (TNBC) presents unique therapeutic challenges.

Purpose of the Study:

  • To investigate the effects of a CDK8 inhibitor on the MDA-MB-468 triple-negative breast cancer cell line.
  • To elucidate the molecular mechanisms underlying CDK8 inhibition in TNBC cells.

Main Methods:

  • Treatment of MDA-MB-468 cells with a CDK8 inhibitor.
  • Assessment of phosphorylation of CDK8 substrates, including E2 promoter binding factor 1 (E2F1) and signal transducer and activator of transcription 3 (STAT3).
  • Analysis of luciferase reporter gene expression, p73 and myeloid cell leukemia sequence 1 (Mcl-1) protein levels, and STAT3 knockdown effects.

Main Results:

  • CDK8 inhibition decreased E2F1 and STAT3 phosphorylation.
  • Increased luciferase expression in E2F1-responsive cells was observed.
  • CDK8 inhibition led to increased p73 and decreased Mcl-1 expression.
  • STAT3 knockdown counteracted the effects of CDK8 inhibition on Mcl-1.

Conclusions:

  • CDK8 inhibitor treatment modulates apoptosis-related proteins p73 and Mcl-1 in TNBC cells.
  • E2F1 and STAT3 signaling pathways are cooperatively involved in CDK8 inhibitor activity.
  • These findings highlight the therapeutic potential of CDK8 inhibitors against triple-negative breast cancer.
Keywords:
CDK8E2F1Mcl-1STAT3kinase inhibitortriple-negative breast cancer

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