Mouse Mammary Tumor Virus

Abstract

Mouse mammary tumor virus (MMTV) is a betaretrovirus that induces mammary carcinomas in mice. MMTV is transmitted through the germline (endogenous virus) as well as through maternal milk (milk-borne virus). Milk-borne MMTV exploits host immune responses and requires infection and amplification in lymphoid cells through the virally encoded superantigen (Sag). Infected B and T lymphocytes disseminate MMTV to epithelial cells in the mammary gland. MMTV replication is tightly controlled in these various cell types at the transcriptional level through both positive and negative elements in the viral long terminal repeats found at the ends of proviral DNA. Positive regulatory elements include the hormone response element, which binds several types of steroid receptors, as well as the mammary gland enhancer. The negative regulatory elements bind at least two homeodomain-containing proteins, SATB1 and CDP, which repress transcription in different cells and differentiation states to avoid insertional mutagenesis of host cells and the resulting tumors. Loss of repression and hormonal activation of milk-borne MMTV leads to efficient viral transcription in differentiated mammary cells to allow maximal transmission during lactation. Since a virally encoded RNA export protein, Rem, also controls post-transcriptional events, MMTV appears to be a complex retrovirus.