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

retrovirus A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...

like the HTL viruses, HI viruses, and BLV. It belongs to the genus ''

Betaretrovirus ''Betaretrovirus'' is a genus of the ''Retroviridae'' family. It has type B or type D morphology. The type B is common for a few exogenous, vertically transmitted and endogenous viruses of mice; some primate and sheep viruses are the type D. Ex ...

''. MMTV was formerly known as Bittner virus, and previously the "milk factor", referring to the extra-chromosomal vertical transmission of murine breast cancer by adoptive nursing, demonstrated in 1936, by

John Joseph Bittner John Joseph Bittner (February 25, 1904 – December 14, 1961) was a geneticist and cancer biologist, who made many contributions on the genetics of breast cancer research, which were of value, not only in cancer research, but also in a variety of ...

while working at the

Jackson Laboratory The Jackson Laboratory (often abbreviated as JAX) is an independent, non-profit biomedical research institution which was founded by a eugenicist. It employs more than 3,000 employees in Bar Harbor, Maine; Sacramento, California; Farmington, Con ...

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. 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 transmitted vertically via milk from mother to pup. It is contained as a DNA

provirus A provirus is a virus genome that is integrated into the DNA of a host cell. In the case of bacterial viruses (bacteriophages), proviruses are often referred to as prophages. However, proviruses are distinctly different from prophages and these ter ...

integrated in the DNA of milk lymphocytes. The viruses become transported through the gastrointestinal tract to the Peyer's patches where they infect the new host's macrophages, and then lymphocytes. MMTV genome

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

; however, it has recently been established, that MMTV encodes an extra self-regulatory mRNA export protein, Rem, with resemblance to the human immunodeficiency virus ( HIV)

Rev Rev or Rév may refer to: Abbreviations Rev. * Rev., an abbreviation for revolution, as in Revolutions per minute * Rev., an abbreviation for the religious style The Reverend * Rev., the abbreviation for Runtime Revolution, a development environ ...

protein, and is therefore the first complex murine retrovirus to be documented. MMTV codes for the retroviral structural genes and additionally for a

superantigen Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are p ...

. This stimulates T lymphocytes with a certain type of V beta chain in their T cell receptor, which in turn stimulates

B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

proliferation increasing the population of cells that can be infected. During puberty, the virus enters the mammary glands with migrating lymphocytes and infects proliferating mammary gland epithelial cells. 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 A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...

into DNA. This DNA intermediate state of the virus is called the

. When the virus DNA is inserted inside or even near an oncogene, it is able to change the expression of that gene and cause cancer. 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. 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. In addition the expression of the genome is activated specifically in the mammary gland cells. Estrogen is able to further activate the expression of the viral genome. The expression of ''sag'' gene which is present in the provirus is responsible for the production of a superantigen. 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. 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.

Hormonal responsiveness of integrated MMTV DNA

Endogenous MMTV reacts to the whole range of hormones that regulate normal mammary development and lactation, response has been demonstrated to

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

hormones ( androgens, glucocorticoids and

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural product, natural female sex hormone progesterone in the body. A progestin is a ''synthetic co ...

s), as well as prolactin. 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.

The MMTV promoter in models of human breast cancer

The LTR ( long terminal repeat) of MMTV contains a glucocorticoid

hormone response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein binds ...

. 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. The MMTV promoter is used in the PyMT model system of

mouse models of breast cancer metastasis Breast cancer metastatic mouse models are experimental approaches in which mice are genetically manipulated to develop a mammary tumor leading to distant focal lesions of mammary epithelium created by metastasis. Mammary cancers in mice can be cau ...

. Here Py is the abbreviation of polyoma and MT is the abbreviation for middle T. There are more model systems of breast cancer which use the MMTV promoter. The polyoma middle T-antigen is taken from the polyoma virus. The MMTV-PyMT model has been shown to be a reliable model of breast cancer metastasis. In human breast cancer the polyoma middle T- antigen was not found.

Notes

References

* * * * * * * * * {{DEFAULTSORT:Mouse Mammary Tumor Virus Betaretroviruses Rodent diseases Animal viral diseases