Mouse mammary tumor virus
Encyclopedia
Mouse mammary tumor virus (MMTV) is a milk transmitted retrovirus
like the HTL viruses, HI
viruses and BLV
. It belongs to the genus betaretrovirus
es. 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 Dr. John Joseph Bittner
, while working at the Jackson Laboratory
in Bar Harbor, Maine. Dr. Bittner, a geneticist and cancer biologist, 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 Medicine: Cancer Virus The majority of mammary tumors in mice are caused by mouse mammary tumor virus (MMTV).
via milk from mother to pup. It is contained as a DNA provirus
integrated in the DNA of milk lymphocyte
s. The viruses become transported through the gastrointestinal tract to the Peyer's patches where they infect the new host's macrophages, and then lymphocytes.
The mouse mammary tumor virus (MMTV) has formerly been classified as a simple retrovirus
, 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 protein, and is therefore the first complex murine retrovirus to be documented
MMTV codes for the retroviral structural genes and additionally for a superantigen
. This stimulates T lymphocytes with a certain type of V beta chain in their T cell receptor
, which in turn stimulates B cell
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 mouse mammary tumor virus (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 an oncogene
, is able to change the expression of that gene and cause 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. In lymphocytes a T-cell leukemia was shown to occur.
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 [8]. In addition the expression of the genome is activated specifically in the mammary gland cells [8]. 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.
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. [9]
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 in to 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.
hormones, mostly progesterone
, so 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 is all new mammary tissue cells. [9]
The strongest hormone for virus production is the artificial cortisone
dexamethasone
. Dexamethasone is a strong inducer of lactation
and is used for this purpose in the dairy industry.
MMTV has been found in human breast cancer. A complete proviral sequence that was greater than 95% homologous to MMTV was sequenced out of human breast cancer tissue including a correct integration into the human genome. It was named Human Mammary Tumor Virus (HMTV). There has even been a correlation to an increased prevalence of HMTV with gestational breast cancer (62% for gestational BC (=gestational breast cancer) compared with 38% for all BC) indicating that the virus may retain its hormonal regulation. Early indications of MMTV (or MMTV like) virus involvement were confused by the presence of Human Endogenous RetroVirus (HERV) sequences that have a much lower level of homology to MMTV than HMTV. These were traces of one or more viruses similar to MMTV. It is emerging that many human breast cancers contain part of the env gene of a virus that is very close to MMTV. The presence of HMTV (not HERV) sequences has been found by multiple researchers in up to 42% of breast cancers in Europe, North America as well as Australia. This is compared to only 1 to 2% of the healthy population. While some consider the presence of MMTV in humans controversial, there is a large amount of evidence that MMTV (or a VERY close relative) plays a role in some human breast cancers. The env gene sequences are not found in the other cells of the body suggesting that they are of foreign origin. That being said, Garry, Pogo, and Holland all have patented the use of MTV sequences for diagnostic uses in detection of human breast cancer (Pat #’s 6,670,466; 6,040,146; 5,686,247 respectively). Dr. Garry also claims that there is an endogenous version of HMTV in up to 14% of the population in his patent though he has yet to publish a peer reviewed article demonstrating his evidence.
MMTV has also been implicated in other human diseases. In the mouse, MMTV can also cause leukemia. Human breast cancer has been correlated with leukemia in humans and viral sequence has been found in these cancers. A complete proviral sequence has also been sequenced for the lymph nodes of patients with Primary Biliary Cirrhosis. Biliary epithelial cells infected with MMTV convert to the same pathology as those found in PBC patients.
MMTV is an interesting virus for human diseases. It has superantigenic properties which destroy part of the immune system of the infected mouse. The well documented MMTV pathogenesis helps to understand the action of superantigens in human disease.
In the last few years a number of labs have found MMTV like DNA in human breast cancer tissue and most recently, the virus has been shown to be able to productively infect human cells, possibly suggesting that an MMTV like virus may play a role in human breast cancer. It was shown too, that human breast cancer often occurs in areas where Mus domesticus is the prominent species of mice. In the lab, MMTV was shown to readily infect canine and feline tissue culture cells. One theory of how MMTV would be passed to humans is through contact with our pets. Although it is difficult to imagine how modern women would get infected by a mouse virus, an infection of both species by the same food might be a possibility, or passage from one species to the other may also occur. This mode of infection might explain the often seen development of benign or malignant mammary tumors in pets. Dogs and cats are often affected and they too have access to human food and share living space with humans.
) of MMTV contains a glucocorticoid
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.
The MMTV promoter is used in the PyMT model system of breast cancer. Here Py is the abbreviation of polyoma middle T-antigen and MT is the abbreviation for the MMTV promoter. There are more model systems of breast cancer which use the MMTV promoter. The polyoma middle T-antigen is taken from the polyoma virus. In human breast cancer the polyoma middle T- antigen was not found.
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
like the HTL viruses, HI
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
viruses and BLV
Bovine leukemia virus
Bovine leukemia virus is a bovine virus closely related to HTLV-I, a human tumour virus.BLV is a retrovirus which integrates a DNA intermediate as a provirus into the DNA of B-lymphocytes of blood and milk. It contains an oncogene coding for a protein called Tax. Nevertheless in its natural host...
. It belongs to the genus betaretrovirus
Betaretrovirus
A 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....
es. 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 Dr. John Joseph Bittner
John Joseph Bittner
John Joseph Bittner 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 other biological investigations.- Biography :Bittner was born in Meadville, Pennsylvania, on...
, while working at the Jackson Laboratory
Jackson Laboratory
The Jackson Laboratory was founded in Bar Harbor, Maine in 1929 by former University of Maine and University of Michigan president C. C. Little under the name Roscoe B...
in Bar Harbor, Maine. Dr. Bittner, a geneticist and cancer biologist, 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 Medicine: Cancer Virus The majority of mammary tumors in mice are caused by mouse mammary tumor virus (MMTV).
Infection and life cycle
Several mouse strains carry the virus endogenously, but it is also transmitted verticallyVertical transmission
Vertical transmission, also known as mother-to-child transmission, is the transmission of an infection or other disease from mother to child immediately before and after birth during the perinatal period. A pathogen's transmissibility refers to its capacity for vertical transmission...
via milk from mother to pup. It is contained as a DNA provirus
Provirus
A provirus is a virus genome that is integrated into the DNA of a host cell.This state can be a stage of virus replication, or a state that persists over longer periods of time as either inactive viral infections or an endogenous retrovirus. In inactive viral infections the virus will not replicate...
integrated in the DNA of milk lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s. The viruses become transported through the gastrointestinal tract to the Peyer's patches where they infect the new host's macrophages, and then lymphocytes.
The mouse mammary tumor virus (MMTV) has formerly been classified as a simple retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
, 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
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
Rev protein, and is therefore the first complex murine retrovirus to be documented
MMTV codes for the retroviral structural genes and additionally for a superantigen
Superantigen
Superantigens are a class of antigens which cause non-specific activation of T-cells resulting in oligoclonal T cell activation and massive cytokine release...
. This stimulates T lymphocytes with a certain type of V beta chain in their T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
, which in turn stimulates B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
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 mouse mammary tumor virus (MMTV) is able to insert its viral genome in the host genome. The virus RNA genome is reverse transcribed by reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
into DNA. This DNA intermediate state of the virus is called the provirus
Provirus
A provirus is a virus genome that is integrated into the DNA of a host cell.This state can be a stage of virus replication, or a state that persists over longer periods of time as either inactive viral infections or an endogenous retrovirus. In inactive viral infections the virus will not replicate...
. When the virus DNA is inserted inside or even near an oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
, is able to change the expression of that gene and cause 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. In lymphocytes a T-cell leukemia was shown to occur.
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 [8]. In addition the expression of the genome is activated specifically in the mammary gland cells [8]. Estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
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.
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. [9]
Alternatively, pups can be infected vertically
Vertical transmission
Vertical transmission, also known as mother-to-child transmission, is the transmission of an infection or other disease from mother to child immediately before and after birth during the perinatal period. A pathogen's transmissibility refers to its capacity for vertical transmission...
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 in to 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 responds to glucocorticoidGlucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
hormones, mostly progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
, so 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 is all new mammary tissue cells. [9]
The strongest hormone for virus production is the artificial cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
. Dexamethasone is a strong inducer of lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
and is used for this purpose in the dairy industry.
MMTV and human breast cancer
As the infected mice develop mammary tumors in adulthood, MMTV has inspired the search for a human breast cancer virus. While the tumors caused by MMTV are benign and in general do not metastasize in mice. Especially they do not metastasize to the bones as it is typical for human breast cancer and also for the acute leukemia caused by HTLV-I. That makes the virus not useful as a model for human breast cancer, a malignant disease.MMTV has been found in human breast cancer. A complete proviral sequence that was greater than 95% homologous to MMTV was sequenced out of human breast cancer tissue including a correct integration into the human genome. It was named Human Mammary Tumor Virus (HMTV). There has even been a correlation to an increased prevalence of HMTV with gestational breast cancer (62% for gestational BC (=gestational breast cancer) compared with 38% for all BC) indicating that the virus may retain its hormonal regulation. Early indications of MMTV (or MMTV like) virus involvement were confused by the presence of Human Endogenous RetroVirus (HERV) sequences that have a much lower level of homology to MMTV than HMTV. These were traces of one or more viruses similar to MMTV. It is emerging that many human breast cancers contain part of the env gene of a virus that is very close to MMTV. The presence of HMTV (not HERV) sequences has been found by multiple researchers in up to 42% of breast cancers in Europe, North America as well as Australia. This is compared to only 1 to 2% of the healthy population. While some consider the presence of MMTV in humans controversial, there is a large amount of evidence that MMTV (or a VERY close relative) plays a role in some human breast cancers. The env gene sequences are not found in the other cells of the body suggesting that they are of foreign origin. That being said, Garry, Pogo, and Holland all have patented the use of MTV sequences for diagnostic uses in detection of human breast cancer (Pat #’s 6,670,466; 6,040,146; 5,686,247 respectively). Dr. Garry also claims that there is an endogenous version of HMTV in up to 14% of the population in his patent though he has yet to publish a peer reviewed article demonstrating his evidence.
MMTV has also been implicated in other human diseases. In the mouse, MMTV can also cause leukemia. Human breast cancer has been correlated with leukemia in humans and viral sequence has been found in these cancers. A complete proviral sequence has also been sequenced for the lymph nodes of patients with Primary Biliary Cirrhosis. Biliary epithelial cells infected with MMTV convert to the same pathology as those found in PBC patients.
MMTV is an interesting virus for human diseases. It has superantigenic properties which destroy part of the immune system of the infected mouse. The well documented MMTV pathogenesis helps to understand the action of superantigens in human disease.
In the last few years a number of labs have found MMTV like DNA in human breast cancer tissue and most recently, the virus has been shown to be able to productively infect human cells, possibly suggesting that an MMTV like virus may play a role in human breast cancer. It was shown too, that human breast cancer often occurs in areas where Mus domesticus is the prominent species of mice. In the lab, MMTV was shown to readily infect canine and feline tissue culture cells. One theory of how MMTV would be passed to humans is through contact with our pets. Although it is difficult to imagine how modern women would get infected by a mouse virus, an infection of both species by the same food might be a possibility, or passage from one species to the other may also occur. This mode of infection might explain the often seen development of benign or malignant mammary tumors in pets. Dogs and cats are often affected and they too have access to human food and share living space with humans.
The MMTV promoter in models of human breast cancer
The LTR (long terminal repeatLong terminal repeat
Long terminal repeats are sequences of DNA that repeat hundreds or thousands of times. They are found in retroviral DNA and in retrotransposons, flanking functional genes...
) of MMTV contains a glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
hormone response element
Hormone response element
A hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
. 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 breast cancer. Here Py is the abbreviation of polyoma middle T-antigen and MT is the abbreviation for the MMTV promoter. There are more model systems of breast cancer which use the MMTV promoter. The polyoma middle T-antigen is taken from the polyoma virus. In human breast cancer the polyoma middle T- antigen was not found.
Recent scientific publications
- Critical Role for Dendritic Cells in Mouse Mammary Tumor Virus in In Vivo Infection. http://jvi.asm.org/cgi/content/abstract/JVI.02728-06v1
- Mouse mammary tumor virus infects human cells http://cancerres.aacrjournals.org/cgi/content/full/65/15/6651
- Rapid spread of mouse mammary tumor virus in cultured human breast cells http://www.retrovirology.com/content/4/1/73
- Transcription profile of a human breast cancer cell line expressing MMTV-like sequences.http://www.infectagentscancer.com/content/1/1/7
- Viruses and human breast cancer http://www.austrianova.com/CDLGTVD/LawsonMMTV.pdf
- Endogenous MMTV Proviruses Induce Susceptibility to Both Viral and Bacterial Pathogens http://pathogens.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.ppat.0020128
- APOBEC3 inhibits mouse mammary tumour virus replication in vivo. http://www.nature.com/nature/journal/v445/n7130/abs/nature05540.html