Mouse mammary tumor virus explained

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.[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 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.[3] [4]

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.[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. 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.[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.

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),[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.

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.[13] In human breast cancer the polyoma middle T- antigen was not found.[14]

References

Notes and References

  1. Bittner . J. J.. Some Possible Effects of Nursing on the Mammary Gland Tumor Incidence in Mice. 10.1126/science.84.2172.162. Science. 84. 2172. 162. 1936. 17793252. 1936Sci....84..162B. 31163817.
  2. News: Medicine: Cancer Virus. https://web.archive.org/web/20110219235156/http://www.time.com/time/magazine/article/0,9171,934488,00.html. dead. February 19, 2011. TIME magazine. 18 March 1946.
  3. Mertz. JA. Simper, MS . Lozano, MM . Payne, SM . Dudley, JP . Mouse mammary tumor virus encodes a self-regulatory RNA export protein and is a complex retrovirus.. Journal of Virology. December 2005. 79. 23. 14737–47. 16282474. 1287593. 10.1128/JVI.79.23.14737-14747.2005.
  4. Indik. S. Gunzburg, WH . Salmons, B . Rouault, F . A novel, mouse mammary tumor virus encoded protein with Rev-like properties.. Virology. June 2005. 337. 1. 1–6. 15914215 . 10.1016/j.virol.2005.03.040. free.
  5. Reuss. FU. Coffin, JM. Mouse mammary tumor virus superantigen expression in B cells is regulated by a central enhancer within the pol gene. Journal of Virology. July 1998. 72. 7. 6073–82. 9621071. 110413. 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. 10.1128/JVI.72.7.6073-6082.1998.
  6. Golovkina. TV. Dudley, JP . Ross, SR . B and T cells are required for mouse mammary tumor virus spread within the mammary gland. Journal of Immunology. Sep 1, 1998. 161. 5. 2375–82. 10.4049/jimmunol.161.5.2375 . 9725233. 26055839 . 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 . free.
  7. Okeoma. Chioma M.. Lovsin, Nika . Peterlin, B. Matija . Ross, Susan R. . APOBEC3 inhibits mouse mammary tumour virus replication in vivo. Nature. 28 January 2007. 445. 7130. 927–930. 10.1038/nature05540 . 17259974. 2007Natur.445..927O. 4316435.
  8. Michalides. Rob. Wagenaar, Els . Hilkens, John. Hilgers, Jo. Groner, Bernd. Hynes, Nancy . Acquisition of Proviral DNA of mouse mammary tumor virus in thymic leukemi cells from GR mice. Journal of Virology. September 1982. 43. 3. 819–829 . 6292463 . 256192 . 10.1128/JVI.43.3.819-829.1982.
  9. Reuss. F. U.. Coffin, J. M.. The Mouse Mammary Tumor Virus Transcription Enhancers for Hematopoietic Progenitor and Mammary Gland Cells Share Functional Elements. Journal of Virology. 1 September 2000. 74. 17. 8183–7. 10.1128/JVI.74.17.8183-8187.2000. 10933730 . 112353.
  10. Mant. C. Gillett, C . D'Arrigo, C . Cason, J . 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. Jan 5, 2004. 318. 1. 393–404. 14972564. 10.1016/j.virol.2003.09.027. free.
  11. Ham . J. . Thomson . A. . Needham . M. . Webb . P. . Parker . M. . Characterization of response elements for androgens, glucocorticoids and progestins in mouse mammary tumour virus . Nucleic Acids Research . 16 . 12 . 5263–76 . 1988 . 2838812 . 336766 . 10.1093/nar/16.12.5263.
  12. Muñoz . B. . Bolander Jr . F. F. . Prolactin regulation of mouse mammary tumor virus (MMTV) expression in normal mouse mammary epithelium . Molecular and Cellular Endocrinology . 62 . 1 . 23–29 . 1989 . 2545485 . 10.1016/0303-7207(89)90109-3. 40515926 .
  13. Franci. C. Zhou, J . Jiang, Z . Modrusan, Z . Good, Z . Jackson, E . Kouros-Mehr, Hosein . Biomarkers of residual disease, disseminated tumor cells, and metastases in the MMTV-PyMT breast cancer model.. PLOS ONE. 2013. 8. 3. e58183. 23520493. 10.1371/journal.pone.0058183 . 3592916. 2013PLoSO...858183F. free.
  14. Dankort DL, Muller WJ . Signal transduction in mammary tumorigenesis: a transgenic perspective . Oncogene . 19 . 8. 1038–44 . 2000 . 10713687 . 10.1038/sj.onc.1203272.

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