Mouse mammary tumor virus
Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus like the HTL viruses, HI viruses, and BLV. It belongs to the genus Betaretrovirus. 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 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. 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 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.
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. 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. 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 hormones (androgens, glucocorticoids and progestins), 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 is all new mammary tissue cells.
MMTV and human breast cancer
|This section needs additional citations for verification. (December 2007)|
As the infected mice develop mammary tumors in adulthood, MMTV has inspired the search for a human breast cancer virus. The tumors caused by MMTV in mice are benign and in general do not metastasize. 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. Various hypotheses have been discussed for such a possible transmission to humans and the major arguments for and against the involvement of MMTV in human breast cancer has recently been reviewed.
The MMTV promoter in models of human breast cancer
The LTR (long terminal repeat) 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 mouse models of breast cancer metastasis. 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.
- Bittner, J. J. (1936). "Some Possible Effects of Nursing on the Mammary Gland Tumor Incidence in Mice". Science 84 (2172): 162–162. PMID 17793252. doi:10.1126/science.84.2172.162.
- "Medicine: Cancer Virus". TIME magazine. 18 March 1946.
- Mertz, JA; Simper, MS; Lozano, MM; Payne, SM; Dudley, JP (December 2005). "Mouse mammary tumor virus encodes a self-regulatory RNA export protein and is a complex retrovirus.". Journal of Virology 79 (23): 14737–47. PMC 1287593. PMID 16282474. doi:10.1128/JVI.79.23.14737-14747.2005.
- Reuss, FU; Coffin, JM (July 1998). "Mouse mammary tumor virus superantigen expression in B cells is regulated by a central enhancer within the pol gene". Journal of Virology 72 (7): 6073–82. PMC 110413. PMID 9621071.
MMTV encodes a superantigen (Sag) that, when expressed on the surface of B cells or other antigen-presenting cells, activates a large number of T cells by interaction with specific T-cell receptor β chains. The resulting T-cell response in turn stimulates the infected B cells to proliferate and thus amplifies the number of virus-infected cells and potential target bystander cells
- Golovkina, TV; Dudley, JP; Ross, SR (Sep 1, 1998). "B and T cells are required for mouse mammary tumor virus spread within the mammary gland". Journal of Immunology (Baltimore, Maryland) 161 (5): 2375–82. PMID 9725233.
However, the ultimate targets of MMTV are mammary gland cells, which begin dividing during puberty...The infected lymphoid cells then bring virus to the cells of the developing mammary gland, thereby also allowing the virus to overcome its spatial problem... SAg activity is required for efficient viral infection of the mammary epithelial cells and consequent tumorigenesis...Thus, SAg-mediated stimulation of lymphoid cells is needed for their infection and for virus spread between mammary gland cells
- Okeoma, Chioma M.; Lovsin, Nika; Peterlin, B. Matija; Ross, Susan R. (28 January 2007). "APOBEC3 inhibits mouse mammary tumour virus replication in vivo". Nature 445 (7130): 927–930. doi:10.1038/nature05540.
- Reuss, F. U.; Coffin, J. M. (1 September 2000). "The Mouse Mammary Tumor Virus Transcription Enhancers for Hematopoietic Progenitor and Mammary Gland Cells Share Functional Elements". Journal of Virology 74 (17): 8183–8187. doi:10.1128/JVI.74.17.8183-8187.2000.
- Mant, C; Gillett, C; D'Arrigo, C; Cason, J (Jan 5, 2004). "Human murine mammary tumour virus-like agents are genetically distinct from endogenous retroviruses and are not detectable in breast cancer cell lines or biopsies". Virology 318 (1): 393–404. PMID 14972564. doi:10.1016/j.virol.2003.09.027.
- Ham, J.; Thomson, A.; Needham, M.; Webb, P.; Parker, M. (1988). "Characterization of response elements for androgens, glucocorticoids and progestins in mouse mammary tumour virus". Nucleic Acids Research 16 (12): 5263–5276. PMC 336766. PMID 2838812. doi:10.1093/nar/16.12.5263.
- Muñoz, B.; Bolander Jr, F. F. (1989). "Prolactin regulation of mouse mammary tumor virus (MMTV) expression in normal mouse mammary epithelium". Molecular and cellular endocrinology 62 (1): 23–29. PMID 2545485. doi:10.1016/0303-7207(89)90109-3.
- Wang, Y.; Melana, S.M.; Baker, B.; Bleiweiss, I.; Fernandez-Cobo, M.; Mandeli, J.F.; Holland, J.F.; Pogo, B.G.T. (1 January 2003). "High Prevalence of MMTV-like env Gene Sequences in Gestational Breast Cancer". Medical Oncology 20 (3): 233–236. PMID 14514972. doi:10.1385/MO:20:3:233.
- Wang, Y; Jiang, JD; Xu, D; Li, Y; Qu, C; Holland, JF; Pogo, BG (Jun 15, 2004). "A mouse mammary tumor virus-like long terminal repeat superantigen in human breast cancer.". Cancer Research 64 (12): 4105–11. PMID 15205319. doi:10.1158/0008-5472.CAN-03-3880.
- Ford, CE; Faedo, M; Rawlinson, WD (Nov 1, 2004). "Mouse mammary tumor virus-like RNA transcripts and DNA are found in affected cells of human breast cancer.". Clinical cancer research : an official journal of the American Association for Cancer Research 10 (21): 7284–9. PMID 15534103. doi:10.1158/1078-0432.CCR-04-0767.
- Hehlmann, R; Kister, P; Willer, A; Simon, M; Schenk, M; Seifarth, W; Papakonstantinou, G; Saussele, S; Kolb, HJ; Ansari, H (April 1994). "Therapeutic progress and comparative aspects in chronic myelogenous leukemia (CML): interferon alpha vs. hydroxyurea vs. busulfan and expression of MMTV-related endogenous retroviral sequences in CML". Leukemia. 8 Suppl 1: S127–32. PMID 8152279.
- Faschinger, A; Rouault, F; Sollner, J; Lukas, A; Salmons, B; Günzburg, WH; Indik, S (February 2008). "Mouse mammary tumor virus integration site selection in human and mouse genomes". Journal of Virology 82 (3): 1360–7. PMC 2224419. PMID 18032509. doi:10.1128/JVI.02098-07.
- Salmons, B; Günzburg, WH (October 2013). "Revisiting a role for a mammary tumor retrovirus in human breast cancer". International Journal of Cancer 133 (7): 1530–5. PMID 23580334. doi:10.1002/ijc.28210.
- Franci, C; Zhou, J; Jiang, Z; Modrusan, Z; Good, Z; Jackson, E; Kouros-Mehr, Hosein (2013). "Biomarkers of residual disease, disseminated tumor cells, and metastases in the MMTV-PyMT breast cancer model.". PLoS ONE 8 (3): e58183. PMC 3592916. PMID 23520493. doi:10.1371/journal.pone.0058183.
- Dankort DL, Muller WJ: Signal transduction in mammary tumorigenesis: a transgenic perspective. Oncogene 2000, 19:1038– 1044
- Bhadra, Sanchita; Lozano, Mary M.; Payne, Shelley M.; Dudley, Jaquelin P. (1 January 2006). "Endogenous MMTV Proviruses Induce Susceptibility to Both Viral and Bacterial Pathogens". PLoS Pathogens 2 (12): e128. doi:10.1371/journal.ppat.0020128.
- Cammack, Richard; Smith, Anthony Donald; Attwood, Teresa K. et al. (eds.). "Bittner factor or Bittner particle former name for murine mammary tumour virus". Oxford Dictionary of Biochemistry and Molecular Biolog. p. 79.
- Courreges, M. C.; Burzyn, D.; Nepomnaschy, I.; Piazzon, I.; Ross, S. R. (31 January 2007). "Critical Role of Dendritic Cells in Mouse Mammary Tumor Virus In Vivo Infection". Journal of Virology 81 (8): 3769–3777. doi:10.1128/JVI.02728-06.
- Fernandez-Cobo, Mariana; Melana, Stella M; Holland, James F; Pogo, Beatriz GT (1 January 2006). "Transcription profile of a human breast cancer cell line expressing MMTV-like sequences". Infectious Agents and Cancer 1 (1): 7. doi:10.1186/1750-9378-1-7.
- Indik, S. (1 August 2005). "Mouse Mammary Tumor Virus Infects Human Cells". Cancer Research 65 (15): 6651–6659. doi:10.1158/0008-5472.CAN-04-2609.
- Indik, Stanislav; Günzburg, Walter H; Kulich, Pavel; Salmons, Brian; Rouault, Francoise (1 January 2007). "Rapid spread of mouse mammary tumor virus in cultured human breast cells". Retrovirology 4 (1): 73. doi:10.1186/1742-4690-4-73.
- Lawson, JS; Günzburg, WH; Whitaker, NJ (June 2006). "Viruses and human breast cancer". Future Microbiology 1 (1): 33–51. PMID 17661684. doi:10.2217/17460918.104.22.168.
- Levine, Paul H.; Pogo, Beatriz G.-T.; Klouj, Afifa; Coronel, Stephanie; Woodson, Karen; Melana, Stella M.; Mourali, Nejib; Holland, James F. (15 August 2004). "Increasing evidence for a human breast carcinoma virus with geographic differences". Cancer 101 (4): 721–726. doi:10.1002/cncr.20436.