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Updated: Apr 12, 2026
Using Human Differentially Expressed Gene Lists to Perform Downstream Pathway Enrichment Analysis and Target Prioritization
Published on: October 3, 2025
Enriched transcription factor signatures in triple negative breast cancer indicates possible targeted therapies with
Scooter Willis1, Pradip De1, Nandini Dey1
1Avera Cancer Institute, Sioux Falls, SD, United States.
Purpose:
Triple negative (TN) breast cancers which lack expression of the estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors convey a poor prognosis due in part to a lack of targeted therapies.
Methods:
To identify viable targets for the treatment of TN disease, we have conducted a gene set enrichment analysis (GSEA) on seven different breast cancer whole genome gene expression cohorts comparing TN vs. ER + HER2 - to identify consistently enriched genes that share a common promoter motif. The seven cohorts were profiled on three different genome expression platforms (Affymetrix, Illumina and RNAseq) consisting in total of 2088 samples with IHC metadata.
Results:
GSEA identified enriched gene expression patterns in TN samples that share common promoter motifs associated with SOX9, E2F1, HIF1A, HMGA1, MYC BACH2, CEBPB, and GCNF/NR6A1. Unexpectedly, NR6A1 an orphan nuclear receptor normally expressed in germ cells of gonads is highly expressed in TN and ER + HER2 - samples making it an ideal drug target.
Conclusion:
With the increasing number of large sample size breast cancer cohorts, an exploratory analysis of genes that are consistently enriched in TN sharing common promoter motifs allows for the identification of possible therapeutic targets with extensive validation in patient derived data sets.
Insights
Triple negative breast cancer (TNBC) lacks targeted therapies. Gene set enrichment analysis identified NR6A1 as a potential therapeutic target in TNBC, offering new hope for treatment.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) presents a poor prognosis due to a lack of targeted therapies.
- TNBC is defined by the absence of estrogen (ER), progesterone (PR), and HER2 receptors.
Purpose of the Study:
- To identify novel therapeutic targets for triple-negative breast cancer.
- To analyze gene expression patterns in TNBC to find commonalities with other breast cancer subtypes.
Main Methods:
- Gene Set Enrichment Analysis (GSEA) was performed on seven breast cancer cohorts.
- Analysis compared gene expression in TNBC versus ER+ HER2- samples.
- Data from Affymetrix, Illumina, and RNAseq platforms (2088 samples) were utilized.
Main Results:
- GSEA revealed enriched gene expression patterns in TNBC with common promoter motifs.
- Key associated transcription factors include SOX9, E2F1, HIF1A, HMGA1, MYC BACH2, CEBPB, and GCNF/NR6A1.
- NR6A1, an orphan nuclear receptor, was unexpectedly highly expressed in both TNBC and ER+ HER2- samples, indicating its potential as a drug target.
Conclusions:
- Exploratory analysis of consistently enriched genes in TNBC can identify therapeutic targets.
- Common promoter motifs highlight shared regulatory mechanisms across breast cancer subtypes.
- NR6A1 represents a promising, validated drug target for TNBC treatment.
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