Autoimmune Technologies - Applied Biomedical Science

The Inherited Breast Cancer Virus
The Mouse Virus

Mouse mammary tumor virus (MMTV) is a B-type retrovirus. Discovered in 1936, MMTV causes mammary cancer in mice through a process called insertional mutagenesis. A human homolog of MMTV has long been sought by researchers.

The Retrovirus Life Cycle

Unlike most other organisms, the genome of a retrovirus is composed of RNA instead of DNA. This means that infectious retroviral particles contain RNA. After infection of a cell by a retrovirus, the viral RNA is released into the cell along with several proteins which are required for the initial steps of viral replication. One of these proteins is called reverse transcriptase. After the release of the RNA, the reverse transcriptase makes, or transcribes, a DNA copy of the viral genome. This DNA copy is then inserted somewhat randomly into the DNA of the infected cell. The insertions occur in areas of the cell's DNA that are undergoing the normal DNA replication that happens prior to cell division, so only actively growing cells can support insertion of viral DNA. After the DNA copy is inserted into the cell's DNA, viral sequences then direct the expression of the viral genome. During this process, which in the case of MMTV occurs in response to estrogen, a complete RNA copy of the entire viral genome is produced. This RNA is then packaged into infectious viral particles, and the viral particles are subsequently released from the cell where they can infect another cell and start the whole cycle again.

Insertional Mutagenesis

During the viral life cycle the insertion of the viral genome occurs most of the time within "silent" regions of the cell's DNA. These silent regions, which account for the vast majority of the DNA within a cell, have no known function. Sometimes, however, the insertion occurs within or very near the DNA base pairs that make up a gene, and the presence of the virus's inserted DNA alters the function of that gene. The altered gene is said to have been mutated, and this process is called insertional mutagenesis. If the normal function of a gene is critical to the survival of the cell, then a mutation of the gene will kill the infected cell. But if the gene controls a non-critical function of the infected cell, such as its growth, the cell can survive the insertion despite the fact that the cell's physiology has been permanently altered. In some cases this mutation has no outward effect on the cell, but in other cases the mutation can have profound effects on how the cell grows and behaves.

Oncogenes and Cancer

Genes that are susceptible to mutations that cause cancer are called oncogenes. Oncogenes typically control the normal growth and division of cells. During the replication of MMTV, the viral DNA is sometimes inserted within or near a mouse oncogene and changes the function of that gene. Frequently, such mutations result in the formation of a tumor. In mice, about thirty oncogenes have been found that trigger mammary tumor formation after the insertion of the mouse virus's DNA. Because the chances of an insertion occurring within or near an oncogene are low for each virus replication cycle, not all infected cells will become cancerous. However, because rounds of replication and insertion occur over and over again during the lifetime of the mouse in millions of cells, the chances are very good that at some point a mammary tumor will develop. Because this process takes time, MMTV is called a slow-transforming virus.

Inheriting the Virus

During the study of MMTV, researchers found that there are two routes of transmission of the virus in mice. In the first route, the virus is passed from a mother mouse to her pups through her milk. This route is said to be exogenous because the virus passes to the pups outside of the mother. In the second route of transmission, the pups inherit the virus directly from their mother. The pups are infected even without ingesting infected milk, and thus this route of transmission is said to be endogenous. Both routes of transmission result in infected mice, but strains of mice in which the virus has become endogenous usually have higher rates of cancer.

A retrovirus becomes endogenous to an animal after the pro-viral DNA chain, or genome, of the virus is inserted into the DNA of the sperm or egg cell from which the animal happens to be conceived. Once the viral DNA has entered the DNA of the parent's germ cell, the viral DNA is indistinguishable from any other portion of the parent's DNA. After conception, the viral DNA is reproduced every time the embryonic cells divide, and when the baby animal is born, every cell in its body contains the viral DNA. The viral DNA is thus said to be endogenous to the animal. When the animal becomes an adult, every one of its sperm or egg cells will also contain the viral DNA, and the offspring of the animal will inherit the viral DNA in Mendelian fashion, just like any other genetic trait would be inherited.

A mouse with endogenous MMTV thus has the DNA of the virus in every cell of its body. MMTV responds to estrogen, so at puberty all of the mouse's estrogen-sensitive tissues begin to express the virus's messenger RNA. There is an explosion of viral activity that begins at puberty, and for the life of the mouse, every existing and every new mammary tissue cell expresses viral messenger RNA. Insertion of viral DNA is also greatly facilitated by estrogen, which stimulates mammary cells to replicate their DNA and divide, thus providing large numbers of possible insertion sites.

A female mouse with endogenous MMTV is thus somewhat akin to a time bomb. After puberty, every mammary cell of that mouse will contain an active retrovirus which repeatedly inserts copies of its genome randomly within the cell's DNA and in the vicinity of thirty oncogenes. Though MMTV is a slow transforming virus, all of this viral activity in all of these mammary cells makes the odds high that in at least one cell one of the oncogenes will sooner or later become an insertion point. When that does happen, the oncogene will be mutated by the added base pairs of the retrovirus and will begin to create a tumor.

The Endogenous Viruses in the Human Genome

In humans, the DNA chain, or genome, contains about 3 billion base pairs. The human genome contains perhaps 30,000 to 50,000 genes. These genes occupy only about 100 million base pairs, however, and about 2.9 billion base pairs thus represent silent regions of the human genome. Some of these silent base pairs play a structural role, but little is known about most of the silent DNA.

One relatively recent discovery is that the silent regions in humans contain perhaps 50,000 or more endogenous retroviruses and retroviral sequences which have entered the human genome. They are called human endogenous retroviruses, or HERVs, and the majority of these HERVs have some similarity to MMTV.

Significantly, not all humans inherit all HERVs.

The Exogenous Human Homolog of MMTV

There may be both exogenous and endogenous human homologs of HMTV.

Pogo and Holland et al have discovered and won patents for a retrovirus which is more than 95% identical to MMTV. They have found the viral DNA sequences in about 40% of human breast cancer tumors. The Pogo virus is an exogenous virus, because no pro-viral DNA of this virus is present in the blood cells or other normal cells of the breast cancer patients.

In 2000, T.H.M. Stewart et al reported that their epidemiological data showed a close correlation between human breast cancer incidence and mouse ranges, with the highest incidence of human breast cancer worldwide occurring in lands where Mus domesticus is the resident native or introduced species of house mouse. The researchers concluded that humans may be able to acquire MMTV from mice, and the possibility exists that the Pogo virus is such a virus. In 2002, A.F.R. Stewart identified two human genes which produce proteins that are highly related to the MMTV receptor in mice and concluded that transmission of MMTV from mice to humans is a real possibility.

HMTV - The Endogenous Human Homolog of MMTV

Dr. Robert F. Garry, professor of Microbiology and Immunology at Tulane Medical School, has discovered a retrovirus which is also more than 95% identical to MMTV but which is endogenous to humans. Dr. Garry has called his discovery Human Mammary Tumor Virus, or HMTV. HMTV appears to be one of the HERVs. He has also found additional homologs of this virus in cats and in rhesus monkeys.

Dr. Garry has data showing that HMTV DNA sequences appear in about 90% of the human breast cancer patients tested and that the pro-viral DNA appears in the normal blood cells of substantially all of these patients. Dr. Garry has also found the pro-viral DNA of MMTV in the blood cells of approximately 15% of healthy women and men tested. In addition, the data suggests that the number of copies of the virus may be elevated in tumor tissue compared to normal tissue from the same individual. This last finding suggests that HMTV-related tumor formation may result from insertional mutagenesis, and together the data suggests that the 15% of women who have inherited the pro-viral DNA of HMTV may represent a group in which about 90% of breast cancer cases will ultimately arise.

The implications of this finding are dramatic, because they suggest that a blood test which detects the HMTV sequences would be able to tell a woman and her physician whether she was among the small group (about 15%) of women who were very likely to develop breast cancer or among the large group (about 85%) of women who were very unlikely to develop breast cancer. The HMTV-positive women could be monitored aggressively for signs of tumor development, and other prophylactic regimens could perhaps be developed.

In May 2002, Dr. Julian Peto presented data to the Oncogenomics conference in Dublin which suggested that "many, possibly the majority, of breast cancers occur in a minority of women with an inherited risk." According to Dr. Peto, "Identifying and monitoring these susceptible women is going to be an important challenge." Dr. Peto's data was derived from a study of 2,300 sets of identical and non-identical twins.

The Peto study showed that twins of women diagnosed before the age of 40 were at no higher risk of developing breast cancer in later life than twins of patients diagnosed after age 50. Their risk just increased at an earlier age. Dr. Peto said that the data was "all rather puzzling, but it seems breast cancer genes are doing two different things. Some genes act as timer switches, determining when a woman's risk of breast cancer should begin, while other genes dictate how big the risk will be."

Since Dr. Peto and his colleagues had not identified any of the genes of which he spoke, it is a conceptual puzzle rather than a practical puzzle he described. The data is easily explained, however, if the inherited risk is assumed to arise from an MMTV-like HERV instead of from one or more genes, so the Peto findings add support to the Garry findings.

Autoimmune is conducting further studies of HMTV, including studies being done in association with a multinational health care company. Tulane has filed patent applications covering HMTV in the U.S. and other countries.


Garry, R.F. Human Mammary Tumor Virus. In: Where We Stand with Breast Cancer Research (N.J. Agnantis and D.D. Tsiftsis, Eds.) Synedron Press (Athens, Greece), 154-156, 1999.

Garry, R.F. Human Mammary Tumor Virus: An Update. In: Hellenic Society for Breast Cancer Research Symposium Report (N.J. Agnantis, Ed.) Synedron Press (Athens, Greece), 15-19, 2001

Pogo, B.G., Holland J.F. Possibilities of a Viral Etiology for Human Breast Cancer. A review. Biol Trace Elem Res. 1997 Jan;56(1):131-42.

Soble, S., Haislip, A.M., Hill, S.M. and Garry, R.F. Human Sequences Related to Mouse Mammary Tumor Virus. Abstracts of the XIth International Congress of Virology. Sydney Australia. VW44.07 p. 80. 1999.

Stewart, A.F.R. Identification of Human Homologs of the Mouse Mammary Tumor Virus Receptor. Archives of Virology. ArchVirol (2002) 127:577-581

Stewart, T.H.M., Sage, R.D., Stewart, A.F.R., and Cameron, D.W. Breast Cancer Incidence Highest in the Range of One Species of House Mouse, Mus Domesticus. British Journal of Cancer (2000) 82(2). 446-451

This material is not intended to take the place of a physician's advice.


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