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Updated: Jan 31, 2026

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
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BHLHE40 Is a Transcriptional Regulatory Target of NFE2L3 in Triple-Negative Breast Cancer

Shail Rakesh Modi1, Terrick Andey1, George Acquaah-Mensah1

  • 1Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, MA 01608, USA.

Oncology Research
|January 30, 2026
PubMed
Abstract

Insights

Researchers identified Nuclear Factor Erythroid 2-Like 3 (NFE2L3) as a key regulator in triple-negative breast cancer (TNBC). NFE2L3 directly controls Basic Helix-Loop-Helix Family Member E 40 (BHLHE40), impacting TNBC cell proliferation and migration.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Triple-negative breast cancer (TNBC) presents limited therapeutic options and targets.
  • Identifying novel biomarkers and transcriptional regulatory networks (TRNs) is crucial for TNBC treatment.

Purpose of the Study:

  • To identify novel biomarkers and TRNs in TNBC samples.
  • To investigate the regulatory relationship between NFE2L3 and BHLHE40 in TNBC.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) pan-cancer breast cancer (BrCA) datasets.
  • Utilized TRN algorithms and Virtual Inference of Protein-Enriched Regulon (VIPER) to identify master regulators.
  • Validated NFE2L3 and BHLHE40 interactions in TNBC cell lines (MDA-MB-231, MDA-MB-468) using luciferase assays, qRT-PCR, and western blots.

Main Results:

  • Identified NFE2L3 as a master regulator and BHLHE40 as its direct target gene in TNBC.
  • NFE2L3 protein binds to the BHLHE40 promoter, regulating its transcription.
  • NFE2L3 directly controls BHLHE40 expression at transcriptional and translational levels, essential for TNBC cell proliferation and migration.

Conclusions:

  • NFE2L3 plays a significant role in TNBC by regulating the oncogenic activity of BHLHE40.
  • These findings highlight NFE2L3 and BHLHE40 as potential therapeutic targets for TNBC.
Keywords:
Nuclear factor erythroid 2-like 3 (NFE2L3/NRF3)basic helix-loop-helix family member E 40 (BHLHE40/DEC1)master regulatorstranscriptional regulatory networkstriple-negative breast cancer

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