Two research papers - Mouse Mammary Tumor virus in human breast and other cancers

Cancer Res. 2010 May 1;70(9):3576-85. Epub 2010 Apr 13.
Mouse mammary tumor virus-like sequences in human breast cancer.
Lawson JS, Glenn WK, Salmons B, Ye Y, Heng B, Moody P, Johal H, Rawlinson WD,
Delprado W, Lutze-Mann L, Whitaker NJ.
AUSTRALIA
http://www.ncbi.nlm.nih.gov/pubmed/20388779

J Med Virol. 2010 May;82(6):1044-50.
DNA of mouse mammary tumor virus-like virus is present in human tumors
influenced by hormones.
Johal H, Faedo M, Faltas J, Lau A, Mousina R, Cozzi P, Defazio A, Rawlinson WD.
AUSTRALIA
http://www.ncbi.nlm.nih.gov/pubmed/20419820

All research papers courtesy of Karin from PWME forum.

From the Lawson paper;
..."we have confirmed the presence of MMTV-like virus env gene sequences (using PCR and IHC) in ?40% of human breast cancer specimens. Localization of the MMTV env sequences to the nuclei of breast cancer cells supports our previous report (35) and indicates integration of the provirus in human breast cancer. This is important because it indicates a true infection of the breast cancer cells by the MMTV-like virus."

Thanks currer... Very interesting!

I don't understand why they aren't ploughing more resources into potential breast cancer viruses, esp mouse mammary tumor virus... They been finding it for years in breast cancer...

BTW, for anyone else reading, these are 2010 papers, and not newly published.

Here are some interesting snippets from the Johal et al abstract...

This shows that they also found MMTV sequences in prostate cancer samples at 36%:

MMTV-like virus env DNA was detected in ovarian cancers (14/89; 16%), prostate cancers (53/147; 36%), endometrial cancers (5/50; 10%), skin cancers (13/141; 9%) but not in lung cancers (0/51).

And this is familiar, because it suggests that viral expression may be hormonal related, as was suggested with XMRV:

the detection of MMTV-like env sequences in human cancers ... indicates that MMTV-like viral expression is not breast cancer-specific and may relate to hormone-dependent viral expression

Seems like pretty strong stuff, doesn't it?!

Yes, I cant help but wonder if the help we need in investigating the connection between MRVs and human disease will come from the oncologists, as knowledge spreads of the potential for new cancer therapies (based on ARVs.)

It is still true that the prostate cancer papers are unretracted, despite the continued negative attacks on the Lombardi paper. It is easy to undermine one paper by persistent negative investigation. What we need is further courageous and creative broadly based research looking at all the potential disease associations of what these two papers show can reasonably be called "human gamma retroviruses".

CFS/ME is a long way from its proper status as a biomedical disease. It is easy to attack CFS research. It will not be easy to attack cancer research. These papers suggest that up to 1/3 of the human cancers discussed could have an MRV association, and one that might be susceptible to new therapeutic interventions, as we have seen in the case of Dr Snyderman. I suppose this would be dependent on the way the MRV drives the cancer growth. What is true for the way Dr Snyderman's leukaemia may be driven by HGRV multiplication, may not be true for cancers in other tissues.

http://www.x-rx.net/blog/2011/12/update-from-michael-snyderman-md.html
"The retroviruses could induce further changes in gene expression that would make the infected cell line behave in a more malignant fashion. The corollary to this is that treatment that would block viral protein influence in a neoplastic cell line could make the neoplastic cell behave in a less malignant way.

A complementary hypothesis is that infection by HGRV/MLRVs results in a T-cell clonal expansion. The clonal T-cells produce elevated cytokine and chemokine levels which may be partially responsible for the CFS. Furthermore these cytokines and chemokines may have a paracrine activity that would stimulate a simultaneous neoplasm to behave in a more aggressive fashion."

It is also worth remembering that breast and prostate cancer have risen significantly in incidence in the last thirty years, as has leukaemia, all potentially MRV related cancers. So has ovarian cancer, although that underlying rise has been counteracted by success in screening and treatment.
Progesterone appears to be the hormone most responsible for activating the MRVs.

There is currently no medical explanation for the current rise in these cancers, which affect the young as well as the old, and so cannot be related to an aging population.

http://www.ncbi.nlm.nih.gov/pubmed/20388779
"Despite the substantial evidence that MMTV-like virus may have a role in human breast cancer, the development of conclusive evidence has been elusive (2). The reasons include the difficulty in detecting the low levels of MMTV in human breast cancers and concern that the main investigative tool (PCR) may be confounded by false-positive and false-negative results due to sequence variations that affect primer or probe binding"

"Seventy percent of the complete MMTV-like virus genome, identified in human breast cancer specimens and viral particles from human breast metastases, have been sequenced and shown to display 91% to 99% homology to MMTV from mouse mammary tumors. In a recent study, env and long terminal repeat sequences with >98% homology to those of MMTV have been identified in breast cancers that had occurred in a mother, father, and daughter of the same family, living under the same roof "

"A phylogenetic tree was constructed using the sequence data that was obtained (Fig. 3). The phylogenetic tree shows that the MMTV-like virus env gene sequences from human breast cancer, liver diseases, and MMTV from inbred and wild mice interspersed with each other and did not group separately. This confirms the very high homology between MMTV env viral sequences identified in wild and inbred laboratory mice, human liver diseases, and human breast cancer from the United States, Australia, Italy, and Mexico. This indicates that the same MMTV-like virus env sequences are present in mice and humans"

Histologic assessments are also subjective and any similarities may be due to other causes and not necessarily related to MMTV. Again on the other hand, some MMTV-positive IDC breast cancer specimens are so similar to MMTV-positive mouse mammary tumors that at a cellular level, it is not possible to distinguish between the human and mouse tumors. In our opinion, the homology comparisons are probably valid because of the identification of nearly identical MMTV env sequences in breast tumors in women from many different populations with the PCR analyses conducted in different laboratories.

The phylogenetic analyses are in accord with those of Etkind and colleagues (7) who has clearly showed that MMTV-like long terminal repeat nucleotide sequences identified in human breast tumors, human nonHodgkin's lymphomas, and human primary biliary cirrhosis tissues do not cluster as two distinct MMTV species. However, full-length MMTV-like virus sequences from humans have to be compared with full-length MMTV in mice before definitive conclusions can be made about the two viruses being the same, although the envelope genes of retroviruses are known to show the most sequence divergence.

Our current observations in DCIS and IDC breast cancer specimens validate the previous experimental evidence that MMTV can infect, multiply, and randomly integrate into the DNA of normal human breast epithelial cells (810). Together, these data suggest a possible causal role for MMTV-like virus in some human breast cancers. A minority (25%) of invasive human breast tumors have very high levels of similarity to both human medullary type breast cancers and mouse mammary tumors. Therefore, it is possible that MMTV-like virus is associated with this small proportion of human breast tumors despite the consistent finding that MMTV-like virus sequences are present in ?40% of breast tumors."

http://www.ncbi.nlm.nih.gov/pubmed/20388779
Despite the substantial evidence that MMTV-like virus may have a role in human breast cancer, the development of conclusive evidence has been elusive (2). The reasons include the difficulty in detecting the low levels of MMTV in human breast cancers and concern that the main investigative tool (PCR) may be confounded by false-positive and false-negative results due to sequence variations that affect primer or probe binding"

Interesting that the previous quote questions the reliability of straight PCR in assessing infection.

http://www.abrn.net/pdf/2010 Johal.pdf
"This observation in mice together with the detection of MMTV-like virus in skin, ovary, prostate, and endometrial cancer suggests that MMTV-like virus could have a tropism for glandular structures like that found in these tissues."
This quote suggests that the best place to look for MRVs would not be blood, but tissues such as lymph nodes, as has been recently suggested in response to the failure of many researchers to detect MRVs.

"Besides the reported association of MMTV-like virus in human breast cancer, another gammaretrovirus (xenotropic murine leukemia virus-related virus or XMRV) has been detected predominantly in malignant prostate cancers [Schlaberg et al., 2009]. Human endogenous retrovirus K (HERV-K) has also been detected in melanomas [Bu scher et al., 2005].

"HERV-K is a group of endogenous retroviruses that is closely related to MMTV. Despite their similarity, the env gene of MMTV-like virus has been shown to be least homologous to HERV-K10 and primers to this region were used in this study"

http://www.abrn.net/pdf/2010 Johal.pdf
"It is of significance that MMTV-like virus envelope (env) sequences have been detected in human cancers other than breast cancer. This is the first report of MMTV-like virus env in human ovarian, prostate, endometrial, and skin cancersall tumors influenced by local hormonal milieu with varied levels of ER-a andPgR. A pertinent finding is the lack of detection of MMTV-like virus env in human lung cancers. It is proposed that a hormonally active environment is required for MMTV-like viral infection of and/or expression in human cells in vivo."

"Furthermore, MMTV has been shown to productively replicate and spread in human mammary
cells that are hormonally upregulated" [Indik et al., 2005].

I thought there was something recently about breast cancer and these viruses Currer? Maybe I'm just foggy this morrow.

And what could that be, Firestormm?

Presence of MMTV-like env gene sequences in human breast cancer
Beatriz G.-T. Pogo Stella M. Melana
Heberth Moran James F. Holland
Received: 16 August 2010 / Accepted: 13 September 2010 / Published online: 26 September 2010
Springer Science+Business Media, LLC. 2010

To the Editor,

Park et al. 2010 (No evidence of MMTV-like env sequences
in specimens from the Australian Breast Cancer Family
Study, Breast Cancer Research and Treatment online first)
have reported lack of evidence for MMTV-like env gene
sequences in breast cancer specimens from Australia.
We have recently addressed the question of differences
in published results [1, 2] concerning MMTV-like env
sequences in breast cancers. Besides obvious technical
differences such as the ones considered here, there are
major geographical variations in the incidence of breast
cancer and in the frequency of viral sequences in the breast
cancers. Ford et al. [3] reported that 40% of Australian
womens breast cancers contained MMTV-like viral
sequences but none could be detected in specimens from
Vietnam. We have also found 3040% positivity in breast
cancer specimens from four countries in the Americas and
three in Europe, but a sharply lower frequency in breast
cancer specimens from Iran, Japan, and China where breast
cancer is less common [unpublished]. This coordinate
epidemiology of breast cancer and viral presence suggests
a relationship that may turn out to be causal.......

....The suggestion that positive results are due to contamination
indicts many laboratories [310] whose efforts, like
our own, are conducted with utmost care."

It is all very interesting, isn't it currer...
It's a shame that Lipkin isn't testing some prostate cancer samples for MLVs, as well as blood samples from ME patients.

It's interesting that Johal et al found MMTV in 36% of prostate cancer samples. XMRV-positive prostate cancer studies have found XMRV in about 15% to 40% of samples. So is this: Coincidence? Cross reactivity? Multiple MLV infections? Recombinant MLVs? Contamination?

It is also interesting Johal et al found zero viruses in lung cancer, which would suggest that their lab isn't ubiquitously contaminated.

I'm referring to Johal et al.:
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/20419820
Full paper: http://www.abrn.net/pdf/2010 Johal.pdf

MMTV is a betaretrovirus, not a gammaratrovirus as "XMRV" is.

One of these papers suggests that if MMTV is a zoonosis, it could have been transmitted by mouse faeces contaminating grain supplies. Apparently MMTV can infect through the gut lining, and in mice is spread in maternal milk to the young.

"HERV-K is a group of endogenous retroviruses that is closely related to MMTV. Despite their similarity, the env gene of MMTV-like virus has been shown to be least homologous to HERV-K10 and primers to this region were used in this study"

So they do not believe that the MMTV they found could be confused with a HERV.

Odd, given the number of papers that have associated MMTV with human infection that no one suggests a trial of ARV therapies to see if there is any benefit. I wonder why not?
In 2008 over 12,000 deaths from breast cancer in the UK, so current treatment is not doing so well.

Thanks for the titbits of info currer... very interesting.

It is odd that no large scale studies have been done to investigate this.

Some interesting stuff from the Wiki page on MMTV
http://en.wikipedia.org/wiki/Mouse_mammary_tumor_virus


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 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. [9]

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 in to the chromosomal DNA. As a result mice with endogenous MMTV have the viruss 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.

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.[5][citation needed] 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.[6][citation needed] 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[7][citation needed] as well as Australia.[8][citation needed] 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.

MMTV has also been implicated in other human diseases. In the mouse, MMTV can also cause leukemia.[9][citation needed] 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.

It looks from the Wiki page as if human betaretroviruses are thought to exist by many researchers, even though their research faces opposition and it is not yet accepted as orthodoxy.

With a debate continuing about the connection between MMTV and breast cancer, how can human gammaretroviruses be dismissed in such a facile way?

It seems that if HGRVs are accepted for ME, other tumour retroviruses from mice will be waiting in line to be linked with other human diseases. This debate is not just about ME. If mouse retroviruses can be proven to cause one disease, there are other retroviruses that could potentially be causing other diseases. A proportion of the cancers in breast cancer, primary biliary cirrhosis, prostate cancer and leukaemia.

Why is there such resistance to accepting that these "tumor viruses" can have crossed into humans? If breast cancer is caused by a retrovirus, the common house mouse seems to be the source. The infection could easily have passed into the human population historically. Breast cancer is not a new disease, and humans have lives in close contact with mice for centuries. The MMTV can be transmitted by mouse faeces.
http://en.wikipedia.org/wiki/Mouse_mammary_tumor_virus#MMTV_and_human_breast_cancer
http://news.bbc.co.uk/1/hi/health/3879783.stm

My recollection was prompted earlier Currer: http://forums.phoenixrising.me/show...e involvement XMRV pathogenesis breast cancer

There's also a blog here you might like: http://okeefe-lab.blogspot.com/2012/02/evidence-for-xmrv-like-sequence-in.html

I knew I remember 'breasts' from somewhere. Note sure that helps you out though. Sorry.

clearly, there is going to have to be some advancement in finding viruses that are at very low levels. at high levels, they can find viruses in a few days - as lipkin did with SARS and H1N1.

i wonder how many diseases will be solved when they are able to do that. certainly many cancersm lupus and MS will be solved.