Mouse Mammary Tumor Virus Molecular Biology and Oncogenesis

Abstract

Mouse mammary tumor virus (MMTV), which was discovered as a milk-transmitted, infectious cancer-inducing agent in the 1930s, has been used since that time as an animal model for the study of human breast cancer. Like other complex retroviruses, MMTV encodes a number of accessory proteins that both facilitate infection and affect host immune response. In vivo, the virus predominantly infects lymphocytes and mammary epithelial cells. High level infection of mammary epithelial cells ensures efficient passage of virus to the next generation. It also results in mammary tumor induction, since the MMTV provirus integrates into the mammary epithelial cell genome during viral replication and activates cellular oncogene expression. Thus, mammary tumor induction is a by-product of the infection cycle. A number of important oncogenes have been discovered by carrying out MMTV integration site analysis, some of which may play a role in human breast cancer.

The role of BST‐2/Tetherin in host protection and disease manifestation

“…Studies from the Ross Lab have been instrumental in deciphering the roles of restriction factors and other host proteins in Mouse mammary tumor virus (MMTV)‐induced mammary oncogenesis 176, 177, 178, 179, 180. Sequences similar to MMTV are present in human breast tumors 181, 182, 183 and cultures of human breast cancer cells produce human mammary tumor virus (HMTV) with morphologic and molecular characteristics of MMTV and with 95% homology with MMTV 184.…”

Principles and practice of nucleosome positioningin vitro

“…LTRs are duplicated sequences that flank all retroviral genomes, but the MMTV LTR is unusual in having an extended length that encodes a superantigen gene and a hormone-inducible promoter (Ross 2010). The MMTV 5 LTR sits upstream of the viral genome and the promoter drives viral gene transcription, whereas the MMTV 3 LTR is adjacent to mouse genomic sequences and can influence proto-oncogene transcription (Richard-Foy and Hager 1987).…”

Tumorigenesis related to retroviral infections

“…The genomes of simple retroviruses encode the virion capsid/nucleocapsid (Gag) proteins, the enzymes needed for genome replication (reverse transcriptase and integrase; Pol/In), and the envelope proteins (Env) that bind the cell surface molecules used for virus entry [7]. In some instances, simple viruses carry an oncogene or the superantigen gene (Sag) of murine mammary tumor virus (MMTV) [4].…”

“…In some instances, simple viruses carry an oncogene or the superantigen gene (Sag) of murine mammary tumor virus (MMTV) [4]. Conversely, the genomes of complex retroviruses encode non-structural proteins that facilitate virus replication or that counteract intrinsic, innate, or adaptive immune responses during in vivo infection [7].…”

“…Another potential mechanism involves Env binding to Hyaluronidase 2 (Hyal2), Hyal2 degradation, and activation of the RON receptor tyrosine kinase that is normally suppressed by Hyal2 [10,19,24]. Another example of retroviral Env proteins inducing transformation comprises the Env protein (gp55) that is the oncogene of Friend spleen focus-forming virus (SFFV) that induces erythroleukemia in mice [12]; furthermore, the MMTV Env protein has been implicated in mammary tumorigenesis [7]. The Env proteins might reveal other cellular pathways involved in oncogenic transformation [12].…”