Mouse mammary tumor virus

Source: Wikipedia, the free encyclopedia.
Mouse mammary tumor virus
Virus classification Edit this classification
(unranked): Virus
Realm: Riboviria
Kingdom: Pararnavirae
Phylum: Artverviricota
Class: Revtraviricetes
Order: Ortervirales
Family: Retroviridae
Genus: Betaretrovirus
Species:
Mouse mammary tumor virus

Mouse mammary tumor virus (MMTV) is a milk-transmitted

murine breast cancer by adoptive nursing, demonstrated in 1936, by John Joseph Bittner while working at the Jackson Laboratory in Bar Harbor, Maine. Bittner established the theory that a cancerous agent, or "milk factor", could be transmitted by cancerous mothers to young mice from a virus in their mother's milk.[1][2]
The majority of mammary tumors in mice are caused by mouse mammary tumor virus.

Infection and life cycle

Several mouse strains carry the virus endogenously, but it is also

macrophages, and then lymphocytes.[citation needed
]

MMTV genome map

The mouse mammary tumor virus (MMTV) has formerly been classified as a simple

Rev protein, and is therefore the first complex murine retrovirus to be documented.[3][4]

MMTV codes for the retroviral structural genes and additionally for a

T cell receptor, which in turn stimulates B cell proliferation increasing the population of cells that can be infected.[5] During puberty, the virus enters the mammary glands with migrating lymphocytes and infects proliferating mammary gland epithelial cells.[6]

As a retrovirus the MMTV is able to insert its viral genome in the host genome. The virus RNA genome is reverse transcribed by reverse transcriptase into DNA. This DNA intermediate state of the virus is called the provirus. When the virus DNA is inserted inside or even near a gene, it is able to change the expression of that gene and potentially produce an oncogene which might eventually develop into cancer.[7] The viral genome is able to cause cancer only if it alters the expression of an oncogene. If the viral genome is inserted in a "silent" region of the host genome then it is harmless or may cause other diseases. High levels of MMTV are expressed in lymphoid leukemias of mouse strain GR and DBA/2 which contain extra integrated MMTV proviruses. These leukemias are active when cells are transferred to other mice.[8]

When the virus genome is inserted inside the host genome it is then able to transcribe its own viral genes. In F. U. Reuss and J. M. Coffin (2000) experiments it is mentioned that the expression of the virus genome is activated by an enhancer element that is present in the U3 region of the long terminal repeat of the genome.[9] In addition the expression of the genome is activated specifically in the mammary gland cells.[9] Estrogen is able to further activate the expression of the viral genome.[7] The expression of sag gene which is present in the provirus is responsible for the production of a superantigen.[6]

MMTV can be transferred either through an exogenous or endogenous route. If the virus is transferred exogenously, it is passed from the mother mouse to her pups through her milk.[10]

Alternatively, pups can be infected vertically through endogenous infection, inheriting the virus directly from their mother in the germline. Mice that become infected in this way have higher rates of occurrence of tumors. A retrovirus is endogenous to its host once the proviral DNA is inserted into the chromosomal DNA. As a result, mice with endogenous MMTV have the virus's DNA in every cell of its body, as the virus is present in the DNA of the sperm or egg cell from which the animal is conceived.[citation needed]

Hormonal responsiveness of integrated MMTV DNA

Endogenous MMTV reacts to the whole range of

progestins),[11] as well as prolactin.[12]

When the mouse reaches puberty the virus begins to express its messenger RNA in the estrogen sensitive tissues. As a result, after puberty all mammary cells will contain the active retrovirus and begin to replicate in the genome and express viral messenger RNA in all new mammary tissue cells.[10]

The MMTV promoter in models of human breast cancer

The LTR (

hormone response element. This glucocorticoid element is a promoter that is often used to construct mice which develop a breast cancer-like disease, because an animal model system for breast cancer close to the human disease is very much looked for.[citation needed
]

The MMTV promoter is used in the PyMT model system of

polyoma virus. The MMTV-PyMT model has been shown to be a reliable model of breast cancer metastasis.[13] In human breast cancer the polyoma middle T- antigen was not found.[14]

Notes

References