HHV-6 U94 Inhibits Motility, Migration and Invasiveness of Human Breast Cancer Cells by Modulation of Src Signaling Pathway

Cancer metastasis is the most life-treatening aspect of human cancer, being responsible for around 90% of cancer patient mortality. The central, defining process of metastatic disease is the ability of tumor cells to mobilize, invade and cross normally non-permissive tissue barriers. To intravasate, tumors also promote local angiogenesis and lymphangiogenesis by secreting active molecules in the tumor microenvironment capable of inducing endothelial cell (EC) migration and consequently, the pathological formation of new blood vessels. HHV-6 infects ECs and its latency gene U94 inhibits angiogenesis and lymphangiogenesis. Because of its potent anti-migratory activity on ECs, we tested the capability of HHV-6 U94 to interfere with the individual steps of the metastatic cascade, including cancer cell detachment, migration and invasion. We examined the HHV-6 U94 biological activity on the human breast cancer cell line MDA-MB-231 as a model of highly aggressive cancer cell. Here we show that expression of HHV-6 U94 delivered by an HSV-1-based amplicon vector strongly inhibit cell motility and migration, thus affecting cell invasiveness. Moreover, in this study, we show that HHV-6 U94 effects on human breast cancer cells are mediated by the down-modulation of Src signal leading to activation of β-catenin and to a better cell-cell adhesion. We investigated the effects of HHV-6 U94 on cell-cell interactions in a three-dimensional rotary cell-culture system (RCCS). Analysis of MDA-MB-231 cell expressing HHV-6 U94 showed, as expected, a greater aggregation and an increased expression of β-catenin on the cell membrane, compared to control cells.

The capability of HHV-6 U94 to block migratory and invasive property of cancer cells may lead to the development of new therapeutic approaches.