ArticleFrontiers in oncology2026
BRD4 PROTAC degrader enhances fulvestrant sensitivity in ER+ breast cancer via super-enhancer associated GREB1.
Article in Frontiers in oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Breast cancer has the highest incidence and mortality among all cancers affecting women. Fulvestrant resistance remains a major clinical challenge that limits the efficacy of endocrine therapies. BRD4, a transcriptional regulator that recognizes acetylated histones, is implicated in the pathogenesis and progression of various tumors, including breast cancer. However, its role in fulvestrant sensitivity and the therapeutic potential of targeted BRD4 degradation require further investigation. Methods: We assessed BRD4 transcriptional activity in breast cancer and its functional role in tumor progression and endocrine sensitivity. The antitumor effect of a PROTAC-targeted BRD4 degrader, alone or in combination with fulvestrant, was evaluated in breast cancer cells. Integrated analysis of BRD4 and estrogen receptor (ER) chromatin immunoprecipitation sequencing (ChIP-seq) datasets was performed to identify co-occupied genomic regions and downstream targets. GREB1 was identified as a key effector and further validated as a super-enhancer-associated gene. The working mechanism of BRD4 PROTAC and fulvestrant was investigated through GREB1 signaling disruption. Results: The occupancy of BRD4 at promoter regions was found to be increased in breast cancer, and its high expression indicated poor clinical outcome among ER+ breast cancer patients with endocrine therapy. A PROTAC-targeted BRD4 degrader significantly enhanced the antitumor efficacy of fulvestrant in breast cancer cells. Integrated ChIP-seq analysis revealed substantial co-occupancy of BRD4 and ER on shared pathways and identified GREB1 as a critical downstream effector regulated by a BRD4-associated super-enhancer. Mechanistically, the BRD4 PROTAC enhances fulvestrant sensitivity by down-regulation of GREB1 expression. Conclusion: Targeting BRD4 with PROTAC degraders represents a promising therapeutic strategy in breast cancer by suppressing GREB1 expression and enhancing the efficacy of fulvestrant.
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