Since the discovery of Mouse Mammary Tumor Virus (MMTV) as the etiological agent of mammary tumors in mice there have been numerous efforts to determine if a similar agent might be involved in the pathogenesis of human breast cancer. Renewed interest in this issue began in the middle 1990's when we reported that a 660 bp sequence, 9098% homologous to the MMTV envelope (env) gene, with no significant homology to any human gene or human endogenous retrovirus (HERV) nor to any other virus, was detected in 38% (226 of 314) of American women's breast cancers specimens. Similar results have been found across populations from different geographic regions by other laboratories as well as our own. Subsequently a 9.9 kb proviral sequence detected in human breast tumors, amplified, and found to be 95% homologous to MMTV was designated as HMTV. HMTV viral particles with betaretrovirus characteristics have been isolated from primary cultures of metastatic breast cancer cells (MMSM cells) established from pleural and abdominal effusions of patients with metastatic breast cancer. The RNA sequence of these viral particles was 8595% homologous to MMTV. Recently we have shown that HMTV from MSSM cells is able to infect and replicate in primary cultures of human mammary epithelial cells (HMEC), peripheral blood mononuclear cells (PBMC), dendritic cells of healthy donors and the following cell lines: MCF10A, MCF10F, 293T, Ramos (B cells), Jurkat (T cells). In the infected MCF10F cells, expression of proteins characteristic of epithelial cells such as Ecadherin decreased and the expression of proteins characteristic of mesenchymal cells such as Vimentin increased. This phenomenon is typical of the process of Epithelial Mesenchymal Transition observed when healthy epithelial cells become neoplastic. Despite the substantial evidence supporting the presence of HMTV in human breast cancer, controversy continues concerning its relevance and veracity. In addition, the study of murine like viruses in human disease is currently under intense scrutiny and criticism, mainly due to the finding that Xenotropic Murine Leukemia virusrelated virus (XMRV) which was thought to play a role in human prostate cancer and in chronic fatigue syndrome (CFS) now appears to be a mouse contaminant. In this application we propose to demonstrate that HMTV is present in human breast cancer using techniques that can guarantee results free of contamination. If HMTV in breast cancer were the result of murine DNA contamination, it could be determined by this proposed study. Preliminary data using sensitive assays show no detection of murine DNA contamination when HMTV is found. In addition, HMTV has been visualized in the nucleus of breast cancer specimens as well as integrated in chromosomes of MSSM cells. Expansion of these data can provide convincing evidence to the scientific community that HMTV is not a contaminant
In recent years a role for murine like viruses in human disease has come under intense scrutiny and criticism because of the possibility of mouse contamination. In order to answer such criticism for our studies,the presence of Human Mammary Tumor Virus (HMTV), a retrovirus 95% homologous to Mouse Mammary Tumor Virus (MMTV), the etiological agent of breast cancer in mice, must be proven in human breast tumors in the absence of murine contamination. We propose to do this by employing techniques that can guarantee results, which are free from contamination .
