HERV-K env gene promotes tumorigenicity and metastasis through multiple signal pathways, including the Ras/ERK signaling pathway and epithelial-mesenchymal transition (EMT), in breast cancer cells

Background: Overexpression of the human endogenous retrovirus type K (HERV-K) envelope ( env ) gene was demonstrated in various cancers. However, its precise role as a "driver" (initiating tumor development) or "passenger" (simply a consequence of the cancerous state) is still a subject of ongoing research and debate within the scientific community. Methods: The role(s) of HERV-K expression was investigated in multiple cell lines by stably transfecting with the full length HERV-K env gene. Results: Enhanced expression of K-Ras and its activity were detected in normal breast cells after expressing the HERV-K env gene. Enhanced expression of multiple oncogenes was also observed in cancer cells that expressed HERV-K env . Upregulation of expression of EMT markers and beta-Catenin accompanied upregulation of HERV-K expression. Importantly, metastasis to multiple organs was discovered in vivo . Of interest, cancer prevention was demonstrated in mice immunized with HERV-K surface (SU) to a greater extent than with transmembrane protein (TM), due to increased CD8 T cells, decreased Treg cells, and increased Th1 cytokine secretion. Conclusion: The HERV-K env gene is an oncogene that promotes tumorigenesis and metastasis through upregulated expression of the Ras/Raf/MEK/ERK, EMT, and PI3K/AKT pathways. In addition, the HERV-K SU domain but not the TM domain is a tumor-associated antigen (TAA) that can trigger immune responses.