Abstract
PurposeTriple 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. MethodsTo 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. ResultsGSEA 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. ConclusionWith 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.
Highlights
Breast cancer is the most commonly diagnosed cancer in women and second leading cause of cancer-related deaths, statistics that strongly advocate for a better understanding of the mechanisms that drive mammary carcinogenesis (Siegel et al, 2012)
gene set enrichment analysis (GSEA) identified enriched gene expression patterns in Triple negative (TN) samples that share common promoter motifs associated with SOX9, E2F1, HIF1A, HMGA1, MYC BACH2, CEBPB, and GCNF/NR6A1
NR6A1 an orphan nuclear receptor normally expressed in germ cells of gonads is highly expressed in TN and estrogen receptor (ER) + human epidermal growth factor 2 (HER2) − samples making it an ideal drug target
Summary
Breast cancer is the most commonly diagnosed cancer in women (more than 230,000 women were diagnosed with breast cancer in the US last year) and second leading cause of cancer-related deaths, statistics that strongly advocate for a better understanding of the mechanisms that drive mammary carcinogenesis (Siegel et al, 2012). Gene expression profiling has classified breast cancer into intrinsic subtypes (Carey et al, 2006; Sørlie et al, 2001). Among these is the basal-like subtype, representing ER/PRnegative with low HER2 expressing tumors are characterized as the triple negative breast cancer (TNBC). TNBC accounts for approximately 15% of breast cancer diagnoses, but approximately 25% of breast cancer-related deaths due to a more aggressive biology and lack of targeted therapies (Grigoriadis et al, 2012; Dey et al, 2013b). Gene expression data has documented the heterogeneous nature of TNBC (Mayer et al, 2014)
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