@Article{or.2025.070793,
AUTHOR = {Shail Rakesh Modi, Terrick Andey, George Acquaah-Mensah},
TITLE = {<i>BHLHE40</i> Is a Transcriptional Regulatory Target of <i>NFE2L3</i> in Triple-Negative Breast Cancer},
JOURNAL = {Oncology Research},
VOLUME = {34},
YEAR = {2026},
NUMBER = {2},
PAGES = {--},
URL = {http://www.techscience.com/or/v34n2/65580},
ISSN = {1555-3906},
ABSTRACT = { <b>Objectives:</b> The current treatment options and therapeutic targets for triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer (BrCA), are limited. This study aimed to identify novel biomarkers and transcriptional regulatory networks (TRN) inherent in TNBC samples. <b>Methods:</b> We analyzed pan-cancer BrCA datasets from The Cancer Genome Atlas (TCGA) to compare triple-positive breast cancer (TPBC) with TNBC. TRN algorithms and virtual inference of protein-enriched regulon (VIPER) were used to identify master regulators and their target genes. Utilizing TNBC cells (MDA-MB-231 and MDA-MB-468), we validated the relationship of nuclear factor erythroid 2-like 3 (NFE2L3) and basic helix-loop-helix family member E 40 (BHLHE40) by performing a luciferase assay. The expression levels of these targets were measured after transfections with plasmid and siRNA via qRT-PCR and western blots. The effect of these genes on cell proliferation and migration was studied using phenotypic assays. <b>Results:</b> Using computational approaches, we identified <i>NFE2L3</i> as a master regulator with <i>BHLHE40</i> as its target gene. NFE2L3 protein binds to the promoter region of <i>BHLHE40</i> and regulates its transcriptional activity. Additionally, silencing and overexpressing <i>NFE2L3</i> and <i>BHLHE40</i> in TNBC cell lines MDA-MB-231 and MDA-MB-468 showed that <i>NFE2L3</i> directly regulates <i>BHLHE40</i> at both transcriptional and translational levels. We found that BHLHE40 requires NFE2L3 for cell proliferation and migration in TNBC. <b>Conclusion:</b> These findings underscore the significance of <i>NFE2L3</i> and <i>BHLHE40</i> in TNBC, highlighting <i>NFE2L3’s</i> role in regulating the oncogenic activity of <i>BHLHE40</i> in TNBC cells.},
DOI = {10.32604/or.2025.070793}
}