Abstract
BackgroundTriple 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.MethodsGene 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.ResultsAmong 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.ConclusionWe 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.
Highlights
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
We found the Forkhead Box M1 (FOXM1) associated pathway is the top Yin upregulated pathway in TNBC but not in other subgroups of breast cancers
The Peroxisome proliferator-activated receptor (PPARα) associated pathway is the top listed Yang pathway TNBC but is one of the pathways with similar significance shared with other breast cancer subtypes
Summary
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. 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. Of the one million breast cancer cases annually diagnosed around the world, approximately 15–20%, or 170,000, of the cases will be of the Triple-Negative Breast Cancer (TNBC) subgroup [8,9,10]. Similar to breast cancers as a general group, TNBCs exhibit a disparity among racial groups, with premenopausal African and African American women demonstrating higher rates of diagnosis. Other risk factors include increased parity, younger age at first pregnancy, shorter period of breast feeding and higher hip-to-waist ratio [8]
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