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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.
HMTV BIBLIOGRAPHY
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
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