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An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
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BET Bromodomain Inhibition Reverses CDK4/6 Inhibitor Resistance in Estrogen Receptor-Positive Breast Cancer via

Renyan Liu1,2, Xin Wang1, Timothy B Branigan1,2

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 7, 2025
PubMed
Abstract

Insights

Bromodomain and extraterminal domain (BET) inhibition reverses CDK4/6 inhibitor resistance in breast cancer by downregulating CDK6 via miR-34a-5p. This approach, along with miR-34a-5p mimics, shows promise for treating resistant ER+ breast cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • CDK6 overexpression drives acquired resistance to CDK4/6 inhibitors.
  • BRD4's role in recruiting to the CDK6 promoter suggests BET inhibition as a potential therapeutic strategy.

Purpose of the Study:

  • To investigate if bromodomain and extraterminal domain (BET) inhibition can overcome CDK4/6 inhibitor resistance.
  • To elucidate the mechanisms underlying BET inhibitor efficacy in resistant breast cancer models.

Main Methods:

  • Evaluated BET inhibition using cell viability, survival assays, and xenografts in palbociclib-resistant breast cancer cells.
  • Utilized RNA sequencing, luciferase assays, and miRPathDB to identify mediating miRNAs.
  • Assessed the role of continued palbociclib treatment and estrogen receptor alpha expression.

Main Results:

  • BET inhibitors (JQ1, ZEN-3694) downregulated CDK6 and cyclin D1, restoring cell-cycle arrest and inducing apoptosis/tumor regression.
  • BET inhibition decreased CDK6 via miR-34a-5p induction, not direct promoter repression.
  • miR-34a-5p mimics replicated BET inhibitor effects, while inhibitors abrogated them.
  • Continued palbociclib treatment reduced BCL-2 and estrogen receptor alpha, enhancing sensitivity to BET inhibition.

Conclusions:

  • BET inhibition is a viable strategy to reverse CDK4/6 inhibitor resistance in ER+ breast cancers.
  • miR-34a-5p mimics represent a potential therapeutic approach for overcoming resistance.

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