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Background: There is substantial evidence that a virus homologous to mouse mammary tumor virus (MMTV) may have a role in human breast cancer. The present study indicates that those who developed breast cancer associated with an MMTV-like virus had this virus in their non-cancerous breast tissues years before the cancer developed., Methods: Polymerase chain reaction (PCR) techniques and sequencing were used to identify MMTV-like envelope gene sequences (MMTV-like env sequences) in Australian benign breast biopsy specimens from women who several years later developed breast cancer. Murine contamination was excluded by stringent laboratory procedures, and the absence of intracisternal A particle sequences and mitochondrial cyclooxygenase sequences., Results: MMTV-like env sequences (also called HMTV sequences to denote their source) were found in 9 of 25 breast cancer specimens (36%). Among 25 non-cancerous breast biopsies of these same patients taken 1 to 11 years earlier, six contained MMTV-like sequences (24%). Five of the six were among the nine virally-associated breast cancers. In two pairs of specimens, benign and malignant, env sequences were 97% identical., Conclusions: The identification of MMTV (MMTV-like) sequences in breast tissues prior to the development of MMTV positive breast cancer fulfills a key criterion for a possible causal role for the MMTV-like virus in human breast cancer.

Objective: Human mammary tumor virus (HMTV) is 90% to 98% homologous to mouse mammary tumor virus, the etiological agent of mammary tumors in mice. Human mammary tumor virus sequences were found in 40% of the breast cancers studied in both American and Australian women. In addition, 10% of endometrial carcinomas studied in Australian women also contained HMTV sequences. We have explored the possibility that endometrial cancer of American women may also contain HMTV., Methods/materials: Nested polymerase chain reactions, radioactive internal probing, and sequencing were used to establish the presence of unique nucleotide sequences of HMTV in human genomic DNA. The genomic DNAs were tested to guarantee that they were free of murine DNA. Immunohistochemistry with a monoclonal antibody specific for HMTV envelope protein demonstrated that HMTV sequences were translated., Results: Thirteen (23.2%) of 56 of the endometrial cancers studied contained HMTV sequences and proteins. Human mammary tumor virus sequences and protein were not detected in the 33 normal endometria studied., Conclusion: Human mammary tumor virus, an agent with high homology to mouse mammary tumor virus, was found in 23.2% of the endometrial cancers studied, thus opening the possibility of a pathogenic role.

Mouse mammary tumor virus (MMTV) has been related to human breast cancer (BC) in previous studies. Although suggestive sequence homology to MMTV has been described in BC DNA, the presence of human endogenous retroviruses (HERs) confounded these results. We have selected a 660-bp sequence of the MMTV env gene with very low homology to HER or to any other human or viral gene. We have searched for sequences homologous to it using the polymerase chain reaction. DNA was extracted from fresh or frozen tissues using primers and probes constructed to detect 660 bp; for paraffin-embedded tissues, we sought 250-bp sequences by similar methodology. The 660-bp sequence was detected in 121 (38.5%) of the 314 unselected BC samples, in cultured BC cells, in 2 (6.9%) of 29 breast fibroadenomas and in 2 (1.8%) of 107 breast specimens from reduction mammoplastias. The sequence was not found in normal tissues including breast, lymphocytes from BC patients, nor in other human cancers or cell lines. The 250-bp sequence was detected in 60 (39.7%) of the 151 BCs, and in 1 of 27 normal breast samples assayed from paraffin-embedded sections. Cloning and sequencing of the 660 bp and 250 bp demonstrated that they are 95-99% homologous to MMTV env gene, but not to the known HERs nor to other viral or human genes (< 18%). Southern blot analysis using labeled cloned sequences showed that the 660-bp sequences were present in low copy number as a 7-8-kb EcoRI fragment only in breast cancer samples and two breast cancer cell lines that were positive by PCR. These data indicate that 38-40% of human breast cancers contain gene sequences homologous to the MMTV env gene that are absent from other tumors and tissues. These MMTV env gene-like sequences may play a role in the etiology of a large proportion of human breast cancer.

Previous reports showed transactivation of the long terminal repeat (LTR) of HIV-1 in Jurkat cells persistently infected with vaccinia virus. In this communication, electrophoretic mobility shift assays were used to characterize the elements in HIV-1 LTR which might be responsible for the mechanism of transactivation. The results indicated that two elements, those for binding NF-kB and NFAT-1, were able to interact with nuclear extracts derived from Jurkat cells persistently infected with vaccinia virus, suggesting that they may play a role in the transactivation of HIV-1 LTR.