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BRD4 PROTAC degrader enhances fulvestrant sensitivity in ER+ breast cancer via super-enhancer associated GREB1

Xiulei Zhang1, Peiming Zheng2, Zhengyi Liu3

  • 1Department of Central Laboratory, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, China.

Frontiers in Oncology
|June 4, 2026
PubMed
Abstract

Insights

Targeting BRD4 degradation with PROTACs enhances fulvestrant efficacy in breast cancer. This approach suppresses GREB1 expression, overcoming endocrine resistance and improving outcomes for patients with ER+ breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Breast cancer is a leading cause of cancer mortality in women.
  • Fulvestrant resistance is a significant clinical hurdle in endocrine therapy for breast cancer.
  • BRD4, a transcriptional regulator, is implicated in tumor progression, but its role in fulvestrant resistance needs clarification.

Purpose of the Study:

  • To investigate BRD4's role in breast cancer progression and endocrine sensitivity.
  • To evaluate the therapeutic potential of targeting BRD4 degradation in combination with fulvestrant.
  • To elucidate the molecular mechanisms underlying BRD4-mediated regulation of fulvestrant sensitivity.

Main Methods:

  • Assessed BRD4 transcriptional activity and its functional role in breast cancer models.
  • Evaluated the efficacy of a PROTAC-targeted BRD4 degrader combined with fulvestrant.
  • Performed integrated ChIP-seq analysis of BRD4 and ER to identify co-occupied regions and downstream targets, focusing on GREB1.

Main Results:

  • Increased BRD4 occupancy at promoter regions correlates with poor outcomes in ER+ breast cancer patients.
  • A BRD4 PROTAC degrader significantly enhanced fulvestrant's antitumor efficacy.
  • BRD4 and ER co-occupy shared pathways, with GREB1 identified as a key effector regulated by a BRD4-associated super-enhancer.

Conclusions:

  • Targeting BRD4 degradation via PROTACs is a promising strategy for overcoming fulvestrant resistance in breast cancer.
  • This approach enhances fulvestrant sensitivity by down-regulating GREB1 expression.
  • BRD4 targeted degradation offers a novel therapeutic avenue for endocrine-resistant breast cancer.
Keywords:
BRD4GREB1PROTACbreast cancerfulvestrant sensitivity

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