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Updated: Feb 16, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
The exploration of contrasting pathways in Triple Negative Breast Cancer (TNBC)
Shavira Narrandes1, Shujun Huang1,2, Leigh Murphy3,2
1Research Institute of Oncology and Hematology, CancerCare Manitoba & University of Manitoba, Winnipeg, Canada.
Background:
Triple Negative Breast Cancers (TNBCs) lack the appropriate targets for currently used breast cancer therapies, conferring an aggressive phenotype, more frequent relapse and poorer survival rates. The biological heterogeneity of TNBC complicates the clinical treatment further. We have explored and compared the biological pathways in TNBC and other subtypes of breast cancers, using an in silico approach and the hypothesis that two opposing effects (Yin and Yang) pathways in cancer cells determine the fate of cancer cells. Identifying breast subgroup specific components of these opposing pathways may aid in selecting potential therapeutic targets as well as further classifying the heterogeneous TNBC subtype.
Methods:
Gene expression and patient clinical data from The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used for this study. Gene Set Enrichment Analysis (GSEA) was used to identify the more active pathways in cancer (Yin) than in normal and the more active pathways in normal (Yang) than in cancer. The clustering analysis was performed to compare pathways of TNBC with other types of breast cancers. The association of pathway classified TNBC sub-groups to clinical outcomes was tested using Cox regression model.
Results:
Among 4729 curated canonical pathways in GSEA database, 133 Yin pathways (FDR < 0.05) and 71 Yang pathways (p-value <0.05) were discovered in TNBC. The FOXM1 is the top Yin pathway while PPARα is the top Yang pathway in TNBC. The TNBC and other types of breast cancers showed different pathways enrichment significance profiles. Using top Yin and Yang pathways as classifier, the TNBC can be further subtyped into six sub-groups each having different clinical outcomes.
Conclusion:
We first reported that the FOMX1 pathway is the most upregulated and the PPARα pathway is the most downregulated pathway in TNBC. These two pathways could be simultaneously targeted in further studies. Also the pathway classifier we performed in this study provided insight into the TNBC heterogeneity.
Insights
Triple Negative Breast Cancer (TNBC) exhibits aggressive traits due to a lack of therapeutic targets. This study identifies key Yin and Yang pathways, like FOXM1 and PPARα, to better classify TNBC subtypes and guide future treatments.
Area of Science:
- Oncology
- Bioinformatics
- Systems Biology
Background:
- Triple Negative Breast Cancer (TNBC) presents significant clinical challenges due to its aggressive nature, frequent relapse, and poorer survival rates.
- The biological heterogeneity of TNBC complicates treatment strategies, necessitating novel approaches for classification and targeted therapy.
- Current breast cancer therapies are ineffective against TNBC due to the absence of specific molecular targets.
Purpose of the Study:
- To explore and compare biological pathways in TNBC versus other breast cancer subtypes using an in silico approach.
- To investigate the hypothesis that opposing Yin and Yang pathways influence cancer cell fate.
- To identify TNBC subgroup-specific pathway components for potential therapeutic targeting and improved classification.
Main Methods:
- Utilized gene expression and clinical data from TCGA and METABRIC databases.
- Employed Gene Set Enrichment Analysis (GSEA) to identify cancer-enriched (Yin) and normal-enriched (Yang) pathways.
- Performed clustering analysis to compare TNBC pathways with other breast cancer subtypes and Cox regression to associate pathway-defined subgroups with clinical outcomes.
Main Results:
- Identified 133 Yin and 71 Yang pathways significantly enriched in TNBC.
- FOXM1 emerged as the top upregulated (Yin) pathway, and PPARα as the top downregulated (Yang) pathway in TNBC.
- TNBC subtypes, classified using these key Yin and Yang pathways, demonstrated distinct clinical outcome profiles, revealing six unique TNBC subgroups.
Conclusions:
- First report highlighting FOXM1 as the most upregulated and PPARα as the most downregulated pathway in TNBC.
- Suggests simultaneous targeting of FOXM1 and PPARα pathways as a potential therapeutic strategy for TNBC.
- The developed pathway classifier offers valuable insights into TNBC heterogeneity and aids in refining TNBC subtyping for personalized treatment approaches.
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