BET Bromodomain Inhibition Reverses CDK4/6 Inhibitor Resistance in Estrogen Receptor-Positive Breast Cancer via Induction of miR-34a-5p.

ABSTRACT:

Purpose

CDK6 overexpression is one critical determinant of acquired CDK4/6 inhibitor resistance. Because BRD4 is recruited to the CDK6 promoter, we investigated the potential of bromodomain and extraterminal domain (BET) inhibition to reverse CDK4/6 inhibitor resistance.

Experimental design

Cell viability and survival assays and cell line xenografts were used to evaluate BET inhibition in palbociclib-resistant breast cancer cells. Vehicle- and BET inhibitor-treated cells were subjected to RNA sequencing. CDK6 promoter activity was assessed with luciferase assays, and the miRPathDB version 2.0 database was used to identify potential miRNA mediating the effects of BET inhibition. Experiments were conducted to determine whether continued palbociclib treatment is essential for BET inhibitor efficacy and to explore associated mechanisms.

Results

In CDK4/6 inhibitor-resistant models overexpressing CDK6, a cell-cycle gene signature was differentially downregulated following BET inhibition. The BET inhibitors JQ1 and ZEN-3694 reduced the expression of CDK6 and cyclin D1, reinstated CDK4/6 inhibitor-induced cell-cycle arrest, and triggered apoptosis in vitro, as well as tumor regression in vivo. Mechanistically, BET inhibition downregulated CDK6 expression through the induction of miR-34a-5p, rather than by directly repressing the CDK6 promoter. Introduction of a miR-34a-5p inhibitor abrogated BET inhibitor-mediated molecular changes, whereas a miR-34a-5p mimic replicated the effects of BET inhibition. Lastly, resistant cells exhibited downregulation of BCL-2 in the presence of continued palbociclib, associated with reduced estrogen receptor alpha expression, facilitating sensitivity to BET inhibition.

Conclusions

Our findings highlight BET inhibition or the application of miR-34a-5p mimics as promising strategies to reverse CDK4/6 inhibitor resistance in a subset of ER+ breast cancers.

SUBMITTER: Liu R 

PROVIDER: S-EPMC12596151 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature