PVRL4/Nectin-4 is a marker for poor survival and metastasis in breast cancers and is a target for oncolytic therapy

We recently discovered that vaccine and wild type strains of measles virus target a tumor marker on breast cancer cells. This is a receptor protein to which measles virus attaches to initiate infection and it is called PVRL4 (also known as Nectin 4). PVRL4 is very highly expressed all over the surfaces of invasive breast cancer cells but is hardly expressed on normal epithelial cells, making it an excellent target for measles virus mediated killing of tumor cells. Our work shows that the expression of PVRL4 is highly characteristic of very invasive types of breast cancers that spread rapidly throughout the body. PVRL4 is also shed from the cancer cells into the blood, making it a very good diagnostic tool for monitoring the spread and growth of breast cancer. We propose to study PVRL4 as a diagnostic marker for breast cancer, and also test it as a target for the killing of tumor cells by measles virus. The virus-killing (oncolytic) properties of measles virus will be tested in mouse tumor models and subsequently validated in dogs that have breast cancer. The frequency and prevalence of PVRL4/Nectin-4 as a tumor cell marker in human patient breast carcinomas and breast cancer stem cells.Preliminary evidence in our laboratory indicate that most breast cancer cell lines (MCF7, MDA-MB-468, T47D, SKBR3) express PVRL4/Nectin-4 on their cell surfaces and are susceptible to infection by measles virus. Microarrays of human patient breast tumors and breast cancer stem cells indicate that PVRL4/Nectin-4 expression is upregulated in most of these samples. This data will be analyzed and the degree of PVRL4/Nectin-4 expression will be correlated with tumor invasiveness and patient outcome.Testing oncolytic effects of measles virus vaccine strains in mouse breast tumor models.We have already evaluated measles virus infections in nude mice containing human xenograft tumors derived from MDA-MB-468 cells using luciferase bioluminescence imaging. Tumors derived from breast cancer stem cells can be propagated in NOD/SCID mice and will be tested for oncolytic susceptibility to recombinant measles virus. Finally the contribution of the immune system to oncolysis will be evaluated with a 4T1 syngeneic mouse tumor model.