Evidence of another human exogenous retrovirus in breast cancer?

Bob

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This is some research from Dec 2000, that I've just come across, which is suggesting that breast cancer might be caused, in part, by a human retrovirus; the 'human homologue of the mouse mammary tumour virus' (HHMMTV).

http://breast-cancer-research.com/content/3/2/81

"In 1943, Bittner [1] demonstrated three cofactors in the development of spontaneous mammary tumours in mice. These were inherited susceptibility, hormonal influences, and a transmissible influence in mother's milk. This transmissible influence has since been shown to be a retrovirus, now known as the mouse mammary tumor virus (MMTV)."

"In 1971, Moore et al [2] demonstrated that human milk from women who are at high risk for breast cancer contains particles that are morphologically similar to the MMTV ... Evidence has since accumulated showing the presence of a retrovirus that is homologous to MMTV in human breast cancer tissues..."

"It is possible that HHMMTV is transmitted as particles (virions) in mother's milk and as part of the endogenous viral genome in the germline. Given the precedence of the association between MMTV and murine cancer, it is also possible that the exogenous HHMMTV (as virions in human maternal milk) may combine with endogenous HHMMTV, which then has a carcinogenic influence. Given the strong evidence against a human milk-borne infectious agent, it may be that viral human breast carcinogenesis only occurs if the endogenous virus is present in the genome of the breast epithelial cells, in addition to the exogenous virus that may be present in breast milk. Diets with high intakes of energy may lead to increased levels of oestrogen and other hormones that may enhance expression of HHMMTV."

"Many of these possibilities were suggested nearly 30 years ago [45]. At that time there was concern that, if there was a human breast cancer virus that had the milk-transmitted and inherited characteristics of the MMTV, then primary prevention would probably be useless in the face of immunological tolerance. However, if the above hypotheses are shown to be true, then there is a possibility of primary prevention by dietary intervention aimed at a reduction in serum oestrogens, vaccine immunization for viral infections and the use of hormone-modifying agents such as tamoxifen for women with HHMMTV [46]."
Am I missing something here?
I don't totally understand it... Are they saying that HHMMTV is primarily an endogenous or an exogenous virus? And if it is both, then what are the implications?

I don't totally understand it because it looks like HHMMTV might be both endogenous and exogenous...
So is it another HERV (human endogenous retrovirus) that expresses itself fully to form an exogenous virus, which I didn't think was possible for HERV's, or is it a new exogenous human retrovirus?

Has anyone got any insight into this?

A lot of research seems to end up quietly disappearing after it can't be replicated, so maybe it is one of those studies... I haven't looked up any further research studies on the subject yet.
 

anciendaze

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...Am I missing something here?
I don't totally understand it... Are they saying that HHMMTV is primarily an endogenous or an exogenous virus? And if it is both, then what are the implications?

I don't totally understand it because it looks like HHMMTV might be both endogenous and exogenous...
So is it another HERV (human endogenous retrovirus) that expresses itself fully to form an exogenous virus, which I didn't think was possible for HERV's, or is it a new exogenous human retrovirus?

Has anyone got any insight into this?

A lot of research seems to end up quietly disappearing after it can't be replicated, so maybe it is one of those studies... I haven't looked up any further research studies on the subject yet.
This is indeed an example which is used when researchers like Weiss talk about 'rumor viruses'. The problem is that nobody ever seems to get to the bottom of the subject; all they do is falsify some simple hypothesis without enlightening us further. The idea that breast cancer is the result of an exogenous virus may be one of these.

There is a rule of thumb here that ERVs entered the germ line over many, many years, perhaps even millions of years, and no longer cause disease in species that carry them. For the majority of individuals in a species this seems to be true. However, there is a big catch in this reasoning when you are dealing with a single interconnected human population of billions: there are more possibilities in that population than you can ever test in controlled experiments with any laboratory animal; the sheer scale defeats you.

Another rule of thumb is that ERV sequences in the genomes have been mutated to the point they are not competent to reproduce functional virions. This says even when you see particles in a host they are not signs of disease. These things do turn up, and when they do they are disregarded.

Now we have a new generation of researchers with new tools and the persistence to keep looking. One discovery is that a retrovirus like HIV can sometimes activate genes in HERVs. This does not create a new virus, it simply allows that gene to participate in the infectious disease. Other researchers are finding extensive evidence of recombination of sequences in retroviruses. These sequences may come from host sequences, including possible ERVs, or they may come from other infections in the same host.

A chronic disease need not behave like the familiar model of infectious disease with a simple etiology. When it comes to pathological processes which take place over some 30 years, we have no reliable animal models to study. Even if we did have such models, it is easy to miss the one case in 1000 which would mean millions of human victims.

From a standpoint of sociology of science, you can see that the first discoveries in a field are likely to be the easy ones. Researchers who make a string of discoveries by following a few simple rules become objects of emulation. Their rules of thumb which led them to the easy discoveries become enshrined in textbooks as principles, often without mention of the problems in applying them. Nature does not read textbooks, and is under no obligation to obey these rules.

We are at a time when the simple pat answers are no longer enough. To follow the trail further it is necessary to consider things previously ruled out. Interaction between endogenous and exogenous virus, or between distinct exogenous viruses, is a major complication which will have to be considered. Limited progress in treatment of HIV infection may be the result of ignoring such interactions. A disease which requires transfer of significant quantities of fluids for contagion could easily involve more than one infectious agent.
 

lansbergen

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Now we have a new generation of researchers with new tools and the persistence to keep looking. One discovery is that a retrovirus like HIV can sometimes activate genes in HERVs. This does not create a new virus, it simply allows that gene to participate in the infectious disease.

Other researchers are finding extensive evidence of recombination of sequences in retroviruses. These sequences may come from host sequences, including possible ERVs,

Their rules of thumb which led them to the easy discoveries become enshrined in textbooks as principles, often without mention of the problems in applying them. Nature does not read textbooks, and is under no obligation to obey these rules.

We are at a time when the simple pat answers are no longer enough. To follow the trail further it is necessary to consider things previously ruled out. Interaction between endogenous and exogenous virus, or between distinct exogenous viruses, is a major complication which will have to be considered. Limited progress in treatment of HIV infection may be the result of ignoring such interactions.
Well said.

Not everything is known yet. Nature is not static. Evolution continues.
 

Bob

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This is very interesting... Thanks to 'anciendaze' for finding this...

It's an up-to-date research paper, dated May 2010, on the same subject:
http://onlinelibrary.wiley.com/doi/10.1002/cncr.25179/full

It's a follow-up study to the paper I quoted at the beginning of this thread...
The 'HHMMTV' virus has now been designated 'human mammary tumor virus' (HMTV), and they have been doing further, very interesting, research work on it.

This study has detected viral sequences of the HMTV virus, in inflammatory breast cancer (inflammatory breast cancer is a subset of breast cancers), in 71.5% of women in the USA, and in 73.7% of women in Tunisia. "Normal breasts", tested as the healthy controls, tested at 1.4% positive for the viral sequences.

So, with this research paper published, it looks like this is not one of those 'rumour viruses' that's going to disappear into oblivion...
This research paper has shown that there is consistency in detecting this retrovirus in humans.

It's fascinating, and it looks like a very significant development, so i wonder why we haven't heard more about this in the media? Or have I just missed it?



The authors have found that retroviral sequences with 85% to 95% homology to the mouse mammary tumor virus were present in 40% of the sporadic breast cancers of American women. These sequences were not found in normal breasts or other tumors. A whole proviral structure was detected in 2 tumors. Breast cancer cells in culture were shown to contain and shed betaretroviral particles. This virus was designated human mammary tumor virus (HMTV). The authors have investigated the presence of HMTV sequences in a variety of breast conditions and geographic locations. Here they report that inflammatory breast cancer from American women shows a higher incidence of viral sequences (71%) than sporadic breast cancers. Similar incidence has been found in inflammatory breast cancers from Tunisia, and in gestational breast cancers. Because these conditions represent highly invasive malignancies, it is concluded that HMTV is sometimes associated with a particularly malignant phenotype. Cancer 2010;116(11 suppl):2741–4. 2010 American Cancer Society.
http://onlinelibrary.wiley.com/doi/10.1002/cncr.25179/full
 

anciendaze

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There's another aspect which may not have jumped out at you, inflammatory breast cancer is unusually aggressive. One research goal is to find markers which distinguish aggressive cancers from less dangerous ones, and detect them early, when treatment is likely to help. Even without knowing if it is causing cancer, this is enough to justify research on the virus.

For researchers tracing pathology, a virus associated with aggressive forms is more likely to yield clues to causes. Of course, it may actually be the cause, but so far we don't know.