Molecular impact of Human Endogenous Retrovirus K (HERV-K) on breast cancer progression

Bhattacharyya, Dibyangana
Viruses have left their mark on the human genome over millions of years in the form of human endogenous retroviruses (HERVs). These retroelements inserted themselves into our germline, became inherited in a Mendelian fashion, and now make up 8% of our genome. Owing to the accumulation of defective mutations, the majority of these HERVs are replication incompetent. The most recently integrated and well conserved is HERV-K (HML-2). A number of pro-viral members of HERV-K (HML-2) contain intact ORFs for all its viral polyproteins, including accessory proteins Rec and Np9. High levels of HERV-K expression at the protein and mRNA level have been reported in many different cancers including breast, ovarian and melanoma. Most reports in breast cancer however are limited to the expression of env protein alone. We set out to assess the molecular and functional impact of HERV-K (env and gag) in breast cancer. We analyzed breast cancer cell lines and clinical samples for HERVK expression. Our results show that HERV-K is able to regulate breast cancer cell proliferation, migration and invasion in vitro. In our clinical samples, HERV-K env expression is a predictor of poor overall survival in breast cancer in triple negative breast cancer (TNBC) patients. HERV-K env expression also positively correlates with stromal tumor infiltrating lymphocytes (sTILs) while gag negatively correlates with sTILs. Our data indicates that HERV-K expression contributes to patient survival and relates to pathological features. We also investigated the role of nitric oxide in HER2 amplified breast cancer. To that end, we report that nitrosative stress is an inducer of HERV-K is estrogen receptor (ER) negative breast cancer. Nitric oxide is also able to phosphorylate HER2. Nitric oxide mediated increase in cell migration and invasion is reversed by tyrosine kinase inhibitor lapatinib but does not repress HERV-K expression.
NUI Galway
Publisher DOI
Attribution-NonCommercial-NoDerivs 3.0 Ireland