MMTV and Breast Cancer

Sorry, Hitch. Religion doesnt poison *everything*.

Thanks to the bumbling efforts of ‘respected’ scientists like Judy Mikoivts, we now know that its not religion, but mouse DNA, that poisons everything.

Relatively new readers of ERV are well aware of the fact that all efforts to connect XMRV to any human pathogen have ended up being the result of contamination. Though patient samples from the WPI were contaminated with plasmid in a rather convenient (strategic?) manner, others attempting to find the virus have universally determined that their ‘positive’ results are actually the result of mouse DNA contaminating their samples, their reagents, even their Qiagen columns. ‘XMRV’ only momentarily appeared to be a human pathogen because mouse DNA poisons everything.

But only looooooong-time readers of ERV know that this is not new at all. Though XMRV True Believers like to pretend that the inability to connect a mouse retrovirus to their pet disease is a conspiracy, the fact of the matter is, retrovirologists have been playing this same game, with different viruses, for decades. The most prominent being attempts to connect Mouse Mammary Tumor Virus with human breast cancers.

It makes sense to look. I mean, a mouse retrovirus unquestionably causes breast tumors in mice. Humans get breast tumors. Are any human breast tumors the result of mouse retroviral infection?

The answer?

*shrug*

We dunno. Some labs say ‘Yes.’ Some labs say ‘No.’ Some labs say ‘Maybe?’ And amazingly, this controversy has gone on for years and years and years without anyone getting a death threat.

But, thanks to the XMRV fiasco, we are now acutely aware of the fact mouse DNA poisons everything. Mice have lots of endogenous MMTV viruses. How do we know if the studies connecting MMTV to human breast cancers arent as contaminated as the XMRV papers?

Well, we have to look. And papers where they do a TON of hard work, but dont honestly and critically take mouse DNA contamination as a possible explination for their data are wasting their time an effort. Sad example?

A mouse mammary tumor virus env-like exogenous sequence is strictly related to progression of human sporadic breast carcinoma.

The people involved with this paper are, unquestionably, hard workers. They are also, unquestionably, pathologists, not retrovirologists, and it shows.

What XMRV has taught us is that no matter what technique you use, mouse DNA poisons everything. To be 100% sure that what you are observing is real, you need to 1) sequence all of your putative viruses, 2) BLAST those sequences vs the mouse genome, and 3) map integration sites and verify the flanking DNA is human.

We dont have to ‘guess’ whether sequences are the result of contamination. There are formulas to use and programs to run that tell you whether two sequences are significantly different, or probably the same and the ‘differences’ were just sequencing errors. If you find a sequence in a patient that is 99.99999% identical to a mouse ERV on Chromosome 2, and find a different sequence in that patient in a sample collected 10 years later that is 99.99999% to a mouse ERV on Chromosome 11, that is not ‘viral evolution’. Its your samples being contaminated with mouse DNA. And its fine and dandy to identify integration sites, but if you have to verify that the integration site is a) human and b) makes sense. Thanks to XMRV, we know what to look for, and if you dont look for it, you are wasting your time.

These researchers wasted their time.

Allllll this hard work, trying to find MMTV in human breast tumors. They *did* sequence some bits of the Envelope gene… but didnt tell any of us the sequences. They *did* BLAST their sequences… against the human genome, not mouse. They did *not* map/verify retroviral integration sites.

Allllll this hard work, wasted, because thanks to XMRV, I cant believe any of their other data. Not because they are not competent researchers, not because I think theyre frauds, but because mouse DNA poisons everything.

Comments

  1. #1 John C. Welch
    December 20, 2011

    Mice are evil

  2. #2 Prometheus
    December 20, 2011

    What do you think of this increasingly frequent problem of contamination as a false correlative acting as means of vetting research for high risk of Irving Langmuir’s pathological science?

  3. #3 Justicar
    December 20, 2011

    Wow – let’s see if you can piss off the Hitch crowd (and their hitchlings) and the XMRV crowd at the same time. That should be interesting!

    But I’ll have a go at why you’re wrong: Douglas Adams writes of Mice being the rulers of Earth. This makes them worthy of worship, and thus, mice dna poisons everything because mouse belief (in particular of their ability to influence science by some unseen mechanism – they’re not even in the labs and supposedly contaminating the sample in that lab. HAHAHAHA) a faith position and thus religion.

    Therefore, Hitch was right that it is, in fact, religion that poisons everything. Lab contaminating mice are simply another myth that people believe in on faith.

  4. #4 J-Dog
    December 20, 2011

    You heard it here first: Religious Mice Are Evil.

    And Hitchlings don’t get pissed off – they just destoy you with a few well-chosen words and make you cry like a little girl.

  5. #5 Tristan
    December 20, 2011

    Why does it have to be one or the other? Religion poisons everything, and mouse DNA poisons everything.

  6. #6 Brad Casali
    December 20, 2011

    I worked with MMTV mice for some years, and I never realized that this was even a possibility. Maybe it’s because I’m not a retrovirologist (thank God for that), but stuff like this never crosses my mind.

    What would cross my mind is whether this journal had reviewers who were retrovirologists of this paper. It’s pretty obvious from your excellent critique that this wasn’t the case.

    But, this may not be a bad thing as science should be self-correcting. Hopefully this doesn’t end up like XMRV, but I would hope that other papers would either confirm, refute, or produce detailed critiques outlining possible contamination for this paper.

  7. #7 Bill Door
    December 21, 2011

    The people involved with this paper are, unquestionably, hard workers. They are also, unquestionably, pathologists, not retrovirologists, and it shows.

    I am getting less tolerant of this view as time pases. If you are dealing with a retrovirus, you should learn the relevant retrovirology, and you should talk to the experts. They could have found a collaborator who had done this kind of work before. You can call them ‘hard workers,’ but a major part of science is reading up on your field so that you avoid problems like this. As they say, a month in the lab will save you an hour in the library.

  8. #8 Tristan
    December 21, 2011

    Heh – Bill, you must work in one of those fast-moving fields. Around here, the equivalent saying is 3 years and 3 hours.

  9. #9 Bill Door
    December 21, 2011

    #7 Tristan
    No, that’s probably more like it. However, the saying is deprecated, since no one actually goes to the library anymore. More like “3 years in the lab will save you 30 minutes on PubMed.”
    *******
    I think my previous comment might have been a bit harsh. I have made mistakes in my own research before and wasted huge amounts of time chasing phantoms – and I haven’t even been at this very long. But I feel that in cases like this, where the research has the potential to set off a small public health panic, one should be especially sure (s)he’s right. We’re not talking about a paper on the mating habits of geese, after all. If ERV is right about the worthlessness of this paper, the blame can also be placed on the editor of the journal and possibly the reviewers.

    The bright side is that these authors could possibly go back and do the experiments Abbie suggested, if they still have the samples. It is good that their CISH data shows the probe localizing to specific regions of the nucleus of the MMTV ‘positive’ cells, but it doesn’t replace the necessary controls.

  10. #10 Kathleen Ruddy
    December 21, 2011

    Professor Beatriz Pogo of Mt. Sinai School of Medicine identified HMTV (MMTV equivalent) in ~40% of all human breast cancer specimens she examined. Others have confirmed her findings, most importantly Dr. Polly Etkind of the Sloan Kettering Institute. In addition, Pogo has been able to extract the entire provirus from the breast cancer samples and then infect normal human breast cells in vivo with HMTV, thus proving infectivity in man. Caroline Ford in Australia has found that increasing evidence of HMTV in human breast specimens is associated with an increased risk for, and aggressiveness of, breast cancer. Take a look at the You Tube video “It’s Time To Answer The Question” to learn more from the scientists who are doing this research.

  11. #11 Dr. Kathleen T. Ruddy
    February 23, 2012

    I believe this article provides the human flanking sequences you’re after. Please read and comment. Would appreciate your opinion.

    Mouse Mammary Tumor Virus Infects Human Cells
    Stanislav Indik1,2, Walter H. Günzburg1,2, Brian Salmons3, and Francoise Rouault3
    + Author Affiliations

    1Research Institute for Virology and Biomedicine, University of Veterinary Medicine; 2Christian-Doppler Laboratory for Gene Therapeutic Vector Development; and 3Austrianova Biotechnology GmbH, Vienna, Austria
    Requests for reprints:
    Walter H. Günzburg, Research Institute for Virology and Biomedicine, Veterinaerplatz 1, A-1210 Vienna, Austria. Phone: 431-250-772301; E-mail: walter.guenzburg@vu-wien.ac.at.
    Abstract

    Mouse mammary tumor virus (MMTV) has long been speculated to be involved in human breast cancer and more recently in human primary biliary cirrhosis. Despite complete proviral sequences markedly homologous to MMTV being identified in human breast cancer tissue, no convincing evidence has been presented to date that MMTV can infect human cells. Using both wild-type and a genetically marked virus (MMTV-EGFP), we show here the successful infection of a number of different human cells by MMTV. Furthermore, infection of human cells is shown to be almost as efficient as the infection of murine mammary epithelial cells. Sequencing of PCR products from integrated proviruses reveals that reverse transcription and integration of the viral genome has occurred as expected. Furthermore, sequencing of two independent MMTV proviral integration sites reveal them to be present only in the human and not in the mouse genome. Infection requires an intact MMTV envelope protein and is blocked either by heat inactivation of the virus or by specific neutralizing anti-MMTV serum, ruling out a nonspecific mechanism of viral transfer. Thus, MMTV can infect human cells and this finding provides a possible explanation for the detection by others of MMTV sequences in human breast cancer patients.

  12. #12 Dr. Kathleen T. Ruddy
    February 23, 2012

    Sorry to hog the comment space, but I just finished reading another article that is worth your review. Monroe et al from Univ of Penn (2005) showed that MMTV envelope gene was capable of transforming both murine and human mammary epithelial cells in vivo, producing morphology and invasiveness characteristics of cancer. A portion of the envelope gene, ITAM, appears to be (itself) oncogenic. Reference: JEM, Vol 201, No. 3, February 7, 2005, 431-439.

  13. #13 Epithelial Cancer
    March 21, 2012

    I am getting less tolerant of this view as time pases. If you are dealing with a retrovirus, you should learn the relevant retrovirology, and you should talk to the experts. They could have found a collaborator who had done this kind of work before. You can call them ‘hard workers,’ but a major part of science is reading up on your field so that you avoid problems like this.

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