Background: Metastasis is the major cause of death in breast cancer patients. Although the strategies targeting metastasis have promoted survival, the underlying mechanisms still remain unclear. In this study, we used microarray data of primary breast tumor, tumor derived from bone and liver, and skin metastatic tissue, to identify the key genes and pathways that are involved in metastasis in breast cancer.
Methods: We first calculated the differentially expressed genes (DEGs) between three metastatic tissues and primary tumor tissue, and then used it to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Further, we analyzed the correlation of genes enriched in GO terms and KEGG pathways with survival of breast cancer patients. To identify the key genes and pathways associated with metastasis, we overlapped the DEGs and KEGG pathways. In our in vitro experiments, we knocked down the key gene, ERLIN2 , and detected the PI3K expression in tumor cells to evaluate their effect on tumor metastasis.
Results: We identified six genes (ALOX15 , COL4A6 , LMB13 , MTAP , PLA2G4A , TAT ) that correlated with survival. Seven key genes (SNRPN , ARNT2 , HDGFRP3 , ERO1LB , ERLIN2 , YBX2 , EBF4 ) and seven signaling pathways (metabolic pathways, phagosome pathway, PI3K-AKT signaling pathway, focal adhesion, ECM-receptor interaction, pancreatic secretion, human papillomavirus infection) associated with metastasis were also identified. Our in vitro experiments revealed that ERLIN2  was highly expressed in MDA-MB231 cells compared to MCF-7 cells. Moreover, knockdown of ERLIN2  increased apoptosis, while inhibiting the proliferation, invasion, and migration ability of breast cancer cells. The PI3K/AKT signaling pathway was also found to be highly expressed in MDA-MB231 cells.
Conclusion: Our results reveal the key genes and signaling pathways that contribute to metastasis, and highlight that strategic targeting of ENLIN2  and PI3K/AKT signaling pathways could inhibit metastasis of breast cancer.
Keywords: breast cancer, metastasis, transcriptome microarray data, key genes, signaling pathways