Activation of HERV-K Env protein is essential for tumorigenesis and metastasis of breast cancer cells

Abstract

Human endogenous retrovirus type K (HERV-K) Env protein was previously demonstrated to be overexpressed in human breast cancer (BC) cells and tissues. However, the molecular pathways driving the specific alterations are unknown. We now show that knockdown of its expression with an shRNA (shRNAenv) blocked BC cell proliferation, migration, and invasion. shRNAenv transduction also attenuated the ability of BC cells to form tumors, and notably prevented metastasis. Mechanistically, downregulation of HERV-K blocked expression of tumor-associated genes that included Ras, p-RSK, and p-ERK. The major upstream regulators influenced by HERV-K knockdown were p53, TGF- β1, and MYC. Of interest, when the HERV-K env gene was overexpressed in shRNAenv-transduced BC cells using an HERV-K env expression vector, Ras/Raf/MEK/ERK pathway signaling was restored. CDK5, which alters p53 phosphorylation in some cancers, was upregulated and p53 was downregulated when HERV-K was overexpressed. CDK5 is also a mediator of TGF-β1-induced epithelial-mesenchymal transition and migration in cancer cells, and is involved in tumor formation. Importantly, reductions in migration, invasion, and transformation of BC cells stably transduced with shRNAenv was reversed after adding back a vector with a synonymous mutation of HERV-K env. Taken together, these results indicate that HERV-K Env protein plays an important role in tumorigenesis and metastasis of BC.

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

“…KRAS expression led to activation of JNK in pancreatic cancer cell lines (71). HERV-K control of RAS expression has been reported by us in breast cancer (41,42), and our results in the current study using KRAS mutant Panc-1 cells suggest that HERV-K may induce JNK activation in PCs with KRAS mutation.…”

“…Although HERV-K is the most complete and biologically active family of HERVs, the precise mechanism leading to abnormal HERV gene expression has yet to be clearly understood. Our results below and recent publications [ours (42) (39,41) and others (43)] provide strong evidence that abnormal expression of HERV-K triggers pathological processes leading to cancer onset, and also contributes to the morphological and functional cellular modifications implicated in cancer progression (2–9). HERV-K can express two accessory viral proteins, Rec and NP9, which are believed to have oncogenic potential (44).…”

“…One of six siRNAs (shRNAenv) and its scrambled siRNA (shRNAc) were selected and cloned into the lentivector pGreenPuro (System Biosciences, Palo Alto, CA; sFig. 4D), which contains a green fluorescent protein (GFP) reporter gene, to generate shRNA vectors (shRNAenv) and control vector (shRNAc) as described previously (42). The pairs of shRNA targeting HERV-K that were used in breast cancer cells in this previous study were further tested in PC cells.…”

A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion

“…A number of different transcription factors have been associated with EMT, and this generic term in fact covers several processes that can occur in different circumstances, either in normal development or in the course of disease [30]. Previous studies had already hinted at oncogenic properties for HERV-K Env, but it had only been shown that this Env protein can alter the phenotype of pre-transformed, cancer-derived cell lines [23–25] whereas we demonstrate here that it can also direct non-malignant cells in the path towards transformation. Given the change of the EMT markers and cell motility observed, it is likely that HERV-K Env expression by a tumour or a pre-tumour could also trigger further changes and favour metastasis.…”

Human Endogenous Retroviruses-K (HML-2) Expression Is Correlated with Prognosis and Progress of Hepatocellular Carcinoma

“…The upregulated level of Np9 protein which is coded by type 1 HERV-K promoted the growth of leukemia cells in vitro and in vivo by not only activating ERK, AKT, and Notch1 pathways but also upregulating β -catenin essential for survival of leukemia stem cells [44]. In human breast cancer, the overexpressed HERV-K specifically increases Ras-induced ERK activation, which suggests that the oncogenic activity of Ras protein is propagated by activation of HERV-K Env protein [45]. While the role which this upregulated HERV-K would play in HCC and the underlying signaling pathways are still unknown, we assume that HERV-K could be related to the transformation and tumorigenesis of HCC through Ras signaling pathways due to the detection of activated Ras/Raf/MAPK pathway in HCC [46].…”