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Background Breast cancer has remained the most common malignancy in women over the past two decades. As lifestyle and living environments have changed, alterations to the disease spectrum have inevitably occurred in this time. As molecular profiling has become a routine diagnostic and objective indicator of breast cancer etiology, we analyzed changes in gene expression in breast cancer populations over two decades using The Cancer Genome Atlas database. Methods We performed Heatmap and Venn diagram analyses to identify constantly up- and down-regulated genes in breast cancer patients of this cohort. We used Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to visualize associated functional pathways. Results We determined that three oncogenes,  PD-L2 ,  ETV5 , and  MTOR  and 113 long intergenic non-coding RNAs (lincRNAs) were constantly up-regulated, whereas two oncogenes,  BCR  and  GTF2I , one tumor suppression gene  MEN1 , and 30 lincRNAs were constantly down-regulated. Up-regulated genes were enriched in “focal adhesion” and “PI3K-Akt signaling” pathways, etc., and down-regulated genes were significantly enriched in “metabolic pathways” and “viral myocarditis”. Eight up-regulated genes exhibited doubled or higher expression and the expression of three down-regulated genes was halved or lowered and correlated with long-term survival. Conclusions In this study, we found that gene expression and molecular pathway enrichments are constantly changing with time, importantly, some altered genes were associated with prognostics and are potential therapeutic targets, suggesting that the current molecular subtyping system must be updated to keep pace with this dynamic change.

Gene expression trend changes in breast cancer populations over two decades: insights from The Cancer Genome Atlas database