Author Topic: No evidence for the involvement of XMRV in the pathogenesis of breast cancer  (Read 1061 times)

jemal

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Looks like another study... but read on.

Quote
British Journal of Cancer , (16 February 2012) | doi:10.1038/

No evidence for the involvement of XMRV or MCV in the pathogenesis of breast cancer

G Khan, P S Philip, M Naase and K M I Al Zarouni

Abstract
Background:

The aetiology of breast cancer remains elusive. A viral aetiology has been proposed, but to date no virus has been conclusively demonstrated to be involved. Recently, two new viruses, namely Merkel cell polyomavirus (MCV) and xenotropic murine leukaemia virus-related virus (XMRV) have been identified and implicated in the pathogenesis of Merkel cell carcinoma (MCC) and familial form of prostate cancer, respectively.

Methods:

We examined 204 samples from 58 different cases of breast cancer for presence of MCV or XMRV by PCR. Samples consisted of both malignant and non-malignant tissues. Additionally, we included 6 cases of MCC and 12 cases of prostate cancer as potential controls for MCV and XMRV, respectively.

Results:

All of the breast cancer samples examined were negative for both MCV and XMRV. However, 4/6 MCC and 2/12 prostate cancer samples were found to be positive for MCV and XMRV, respectively. Sequence analysis of the amplified products confirmed that these sequences belonged to MCV and XMRV.

Conclusion:

We conclude that there is no evidence for the involvement of MCV or XMRV in the pathogenesis of breast cancer. What role these viruses have in the pathogenesis of MCC and prostate carcinomas remains to be demonstrated.

http://www.nature.com/bjc/journal/vaop/ncurrent/full/bjc201251a.html
« Last Edit: February 17, 2012, 06:52:14 PM by jemal »

Robyn

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Well I think more studies would be needed.  My mother had breast cancer and I'm HGRV positive.  I also know of several patients with ME who's sister's or mother have had breast cancer too. Coincidence?  I don't think so.

Could we get a boosh on this?
« Last Edit: February 17, 2012, 06:58:57 PM by Robyn »

jemal

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Definitely Robyn. It's very interesting they found XMRV in MCC and prostate cancer though. And it got published.

Robyn

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Definitely Robyn. It's very interesting they found XMRV in MCC and prostate cancer though. And it got published.

Yes it is.

Karin

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There are more than 60 articles that study the link between cancer (usually breast cancer) and mouse retrovriruses, most of them supporting a link between MMTV and breast cancer:

1. Mouse mammary tumor-like virus and human breast cancer.
Glenn WK, ...
Breast Cancer Res Treat. 2010 Oct;123(3):907; author reply 908-9. Epub 2010 Jul
10. No abstract available.
PMID: 20623182

2. Mouse mammary tumor virus-like gene sequences are present in lung patient
specimens.
Trejo-Avila LM, ...
Virol J. 2011 Sep 24;8:451.
PMID: 21943279 Free PMC Article

3. Presence of mouse mammary tumour-like virus gene sequences may be associated
with morphology of specific human breast cancer.
Lawson JS,...
J Clin Pathol. 2006 Dec;59(12):1287-92.
PMID: 16698952 Free PMC Article

4. Mouse mammary tumor virus: new tumor virus or just a rumor virus?
Brower V.
J Natl Cancer Inst. 2009 Mar 4;101(5):293-5. Epub 2009 Feb 24. No abstract
available. Erratum in: J Natl Cancer Inst. 2009 Apr 15;101(8):553.
PMID: 19244171 Free Article

5. Mouse mammary tumor virus-like viral infection and human breast cancer.
Holland JF, Pogo BG.
Clin Cancer Res. 2004 Sep 1;10(17):5647-9. Review. No abstract available.
PMID: 15355888 Free Article

6. MMTV-like env gene sequences in human breast cancer.
Wang Y,...
Arch Virol. 2001;146(1):171-80.
PMID: 11266212

7. [The possibility of the retroviruses participation in human breast neoplasm
induction].
Kriukova IN, Lushnikova AA, Malivanova TF.
Vopr Virusol. 2002 Jul-Aug;47(4):4-9. Review. Russian.
PMID: 12271725

8. Detection of MMTV-like LTR and LTR-env gene sequences in human breast cancer.
Wang Y, Pelisson I, Melana SM, Holland JF, Pogo BG.
Int J Oncol. 2001 May;18(5):1041-4.
PMID: 11295054

9. Presence of MMTV-like env gene sequences in human breast cancer.
Pogo BG, Melana SM, Moran H, Holland JF.
Breast Cancer Res Treat. 2011 Jan;125(1):295-7. Epub 2010 Sep 26. No abstract
available.
PMID: 20872240

10. Of mice, cats, and men: is human breast cancer a zoonosis?
Szabo S, Haislip AM, Garry RF.
Microsc Res Tech. 2005 Nov;68(3-4):197-208. Review.
PMID: 16276516

11. Mouse mammary tumor virus-like gene sequences in breast cancer samples of
Mexican women.
Zapata-Benavides P, ...
Intervirology. 2007;50(6):402-7. Epub 2007 Oct 31.
PMID: 17975321

12. Clonal isolation of different strains of mouse mammary tumor virus-like DNA
sequences from both the breast tumors and non-Hodgkin's lymphomas of individual
patients diagnosed with both malignancies.
Etkind PR, Stewart AF, Dorai T, Purcell DJ, Wiernik PH.
Clin Cancer Res. 2004 Sep 1;10(17):5656-64.
PMID: 15355890 Free Article

13. Mouse mammary tumour-like virus gene sequences and specific breast cancer
morphology.
Glenn WK, Lawson JS, Whitaker NJ.
J Clin Pathol. 2007 Sep;60(9):1071. Epub 2006 Dec 8. No abstract available.
PMID: 17158634 Free PMC Article

14. MMTV-like sequences in human breast cancer: a fluorescent PCR/laser
microdissection approach.
Zammarchi F,...
J Pathol. 2006 Aug;209(4):436-44.
PMID: 16710841

15. Possibilities of a viral etiology for human breast cancer. A review.
Pogo BG, Holland JF.
Biol Trace Elem Res. 1997 Jan;56(1):131-42. Review.
PMID: 9152517

16. Mouse mammary tumor virus-like sequences in human breast cancer.
Lawson JS, ...
Cancer Res. 2010 May 1;70(9):3576-85. Epub 2010 Apr 13.
PMID: 20388779 Free Article

17. The mouse mammary tumor virus-like env gene sequence is not detectable in
breast cancer tissue of Austrian patients.
Witt A, Hartmann B,...
Oncol Rep. 2003 Jul-Aug;10(4):1025-9.
PMID: 12792764

18. Mouse mammary tumor virus-like ENV gene sequences in human breast tumors and
in a lymphoma of a breast cancer patient.
Etkind P, Du J, Khan A, Pillitteri J, Wiernik PH.
Clin Cancer Res. 2000 Apr;6(4):1273-8.
PMID: 10778951 Free Article

19. Mouse mammary tumor virus in human breast cancer red herring or smoking gun?
Mason AL, Gilady SY, Mackey JR.
Am J Pathol. 2011 Oct;179(4):1588-90. Epub 2011 Aug 30. No abstract available.
PMID: 21884676

20. Is mouse mammary tumor virus an etiologic agent of human breast cancer and
lymphoma?
Wiernik PH, Etkind PR.
South Med J. 2006 Feb;99(2):108-10. No abstract available.
PMID: 16509544

21. [Detection of murine mammary tumor virus (MMTV) env gene-like sequences in
breast cancer from Argentine patients].
Melana SM, ...
Medicina (B Aires). 2002;62(4):323-7. Spanish.
PMID: 12325488

22. Expression of mouse mammary tumor virus-like env gene sequences in human
breast cancer.
Wang Y, Go V, Holland JF, Melana SM, Pogo BG.
Clin Cancer Res. 1998 Oct;4(10):2565-8.
PMID: 9796992 Free Article

23. Possible retroviral etiology of human breast cancer.
Labat ML.
Biomed Pharmacother. 1998;52(1):6-12. Review.
PMID: 9755790

24. Search for mouse mammary tumor virus-like env sequences in cancer and normal
breast from the same individuals.
Melana SM, Holland JF, Pogo BG.
Clin Cancer Res. 2001 Feb;7(2):283-4.
PMID: 11234880 Free Article

25. Viruses and human breast cancer.
Lawson JS, Günzburg WH, Whitaker NJ.
Future Microbiol. 2006 Jun;1(1):33-51. Review.
PMID: 17661684

26. No association of mouse mammary tumor virus-related retrovirus with Japanese
cases of breast cancer.
Fukuoka H, Moriuchi M, Yano H, Nagayasu T, Moriuchi H.
J Med Virol. 2008 Aug;80(8):1447-51.
PMID: 18551605

27.[Searching for retroviral sequences related to human breast cancer].
Pogo BG, Holland JF, ...
Medicina (B Aires). 1997;57 Suppl 2:75-80. Spanish.
PMID: 9567345

28. Detection of mammary tumor virus env gene-like sequences in human breast
cancer.
Wang Y, Holland JF, ...
Cancer Res. 1995 Nov 15;55(22):5173-9.
PMID: 7585568 Free Article

29. Human breast cancer and lymphomas may share a common aetiology involving
Mouse Mammary Tumour Virus (MMTV).
Cotterchio M, Nadalin V, Sauer M.
Med Hypotheses. 2002 Oct;59(4):492-4.
PMID: 12208195

30. Mouse mammary tumor virus-like env sequences in human breast cancer.
Mok MT, Lawson JS, Iacopetta BJ, Whitaker NJ.
Int J Cancer. 2008 Jun 15;122(12):2864-70.
PMID: 18348144

31. MMTV-induced mutations in mouse mammary tumors: their potential relevance to
human breast cancer.
Callahan R.
Breast Cancer Res Treat. 1996;39(1):33-44. Review.
PMID: 8738604

32. An unlikely link? Researchers probe viral role in breast cancer.
Ziegler J.
J Natl Cancer Inst. 1997 May 7;89(9):608-10. No abstract available.
PMID: 9150180 Free Article

33. Human, rhesus macaque, and feline sequences highly similar to mouse mammary
tumor virus sequences.
Szabo S, ...
Microsc Res Tech. 2005 Nov;68(3-4):209-21.
PMID: 16276510

34. Mouse mammary tumor virus and the immune system.
Ross SR.
Adv Pharmacol. 1997;39:21-46. Review. No abstract available.
PMID: 9160112

35. Accidental passengers or perpetrators? Current virus-cancer research.
Brower V.
J Natl Cancer Inst. 2004 Feb 18;96(4):257-8. No abstract available.
PMID: 14970272 Free Article

36. The possible involvement of virus in breast cancer.
Amarante MK, Watanabe MA.
J Cancer Res Clin Oncol. 2009 Mar;135(3):329-37. Epub 2008 Nov 14. Review.
PMID: 19009309

37. Detection of the env MMTV-homologous sequences in mammary carcinoma patient
intestine lymphoid tissue.
Lushnikova AA, Kryukova IN, Rotin DL, Lubchenko LN.
Dokl Biol Sci. 2004 Nov-Dec;399:423-6. No abstract available.
PMID: 15717597

38. A viral aetiology for breast cancer: time to re-examine the postulate.
Mant C, Hodgson S, Hobday R, D'Arrigo C, Cason J.
Intervirology. 2004;47(1):2-13. Review.
PMID: 15044830

39. Rapid spread of mouse mammary tumor virus in cultured human breast cells.
Indik S, Günzburg WH, Kulich P, Salmons B, Rouault F.
Retrovirology. 2007 Oct 11;4:73.
PMID: 17931409 Free PMC Article

40. Transcription of human endogenous retroviral sequences related to mouse
mammary tumor virus in human breast and placenta: similar pattern in most
malignant and nonmalignant breast tissues.
Yin H, Medstrand P, Andersson ML, Borg A, Olsson H, Blomberg J.
AIDS Res Hum Retroviruses. 1997 Apr 10;13(6):507-16.
PMID: 9100993

41. Mouse mammary tumor virus-like RNA transcripts and DNA are found in affected
cells of human breast cancer.
Ford CE, Faedo M, Rawlinson WD.
Clin Cancer Res. 2004 Nov 1;10(21):7284-9.
PMID: 15534103 Free Article

42. Increasing evidence for a human breast carcinoma virus with geographic
differences.
Levine PH, Pogo BG, ...
Cancer. 2004 Aug 15;101(4):721-6.
PMID: 15305401 Free Article

43. DNA of mouse mammary tumor virus-like virus is present in human tumors
influenced by hormones.
Johal H, ...
J Med Virol. 2010 May;82(6):1044-50.
PMID: 20419820

44. Mouse mammary tumor virus carrying a bacterial supF gene has wild-type
pathogenicity and enables rapid isolation of proviral integration sites.
Jiang Z, Shackleford GM.
J Virol. 1999 Dec;73(12):9810-5.
PMID: 10559292 Free PMC Article

45. Human murine mammary tumour virus-like agents are genetically distinct from
endogenous retroviruses and are not detectable in breast cancer cell lines or
biopsies.
Mant C, Gillett C, D'Arrigo C, Cason J.
Virology. 2004 Jan 5;318(1):393-404.
PMID: 14972564

46. High prevalence of MMTV-like env gene sequences in gestational breast
cancer.
Wang Y, ...
Med Oncol. 2003;20(3):233-6.
PMID: 14514972

47. Sequences related to mouse mammary tumor virus genome in tumor cells and
lymphocytes from patients with breast cancer.
Crépin M, ... Montagnier L.
Biochem Biophys Res Commun. 1984 Jan 13;118(1):324-31.
PMID: 6320830

48. Identification of a proviral structure in human breast cancer.
Liu B, Wang Y, ...
Cancer Res. 2001 Feb 15;61(4):1754-9.
PMID: 11245493 Free Article

49. Search for DNA of exogenous mouse mammary tumor virus-related virus in human
breast cancer samples.
Bindra A, ... Blomberg J.
J Gen Virol. 2007 Jun;88(Pt 6):1806-9.
PMID: 17485542 Free Article

50. Prevalence and characteristics of the MMTV-like associated breast carcinomas
in Tunisia.
Hachana M, ...
Cancer Lett. 2008 Nov 28;271(2):222-30
PMID: 18639977

51. Human mammary tumor virus in inflammatory breast cancer.
Pogo BG, Holland JF, Levine PH.
Cancer. 2010 Jun 1;116(11 Suppl):2741-4.
PMID: 20503403 Free Article

52. Sequences homologous to the mouse mammary tumor virus env gene in human
breast carcinoma correlate with overexpression of laminin receptor.
Pogo BG, ...
Clin Cancer Res. 1999 Aug;5(8):2108-11.
PMID: 10473094 Free Article

53. Mouse mammary tumor virus infects human cells.
Indik S, Günzburg WH, Salmons B, Rouault F.
Cancer Res. 2005 Aug 1;65(15):6651-9.
PMID: 16061645 Free Article

54. Progression from normal breast pathology to breast cancer is associated with
increasing prevalence of mouse mammary tumor virus-like sequences in men and
women.
Ford CE, Faedo M, Crouch R, Lawson JS, Rawlinson WD.
Cancer Res. 2004 Jul 15;64(14):4755-9.
PMID: 15256443 Free Article

55. Correspondence re: C. Ford, et al. Mouse mammary tumor virus-like gene
sequences in breast tumors of Australian and Vietnamese women. Clin. Cancer
Res., 9: 1118-1120, 2003.
Ford C, Faedo M, Delprado W, Rawlinson W.
Clin Cancer Res. 2004 Jan 15;10(2):802. No abstract available.
PMID: 14760104 Free Article

56. MMTV-related env sequences in human breast tumor.
Stewart A.
Int J Cancer. 2003 Aug 10;106(1):138; author reply 139. No abstract available.
PMID: 12794768

57. Sequence homology of nucleic acids from human breast cancer cells and
complementary DNA's from murine mammary tumor virus and Mason-Pfizer monkey
virus.
Das MR, Mink MM.
Cancer Res. 1979 Dec;39(12):5106-13.
PMID: 227595 Free Article

58. Mouse mammary tumor-like env gene as a molecular marker for breast cancer?
Zangen R, Harden S, Cohen D, Parrella P, Sidransky D.
Int J Cancer. 2002 Nov 20;102(3):304-7. No abstract available.
PMID: 12397656

59. Mouse mammary tumor virus-like gene sequences in breast tumors of Australian
and Vietnamese women.
Ford CE, Tran D, Deng Y, Ta VT, Rawlinson WD, Lawson JS.
Clin Cancer Res. 2003 Mar;9(3):1118-20.
PMID: 12631616 Free Article

60. Mouse mammary tumor-like virus is associated with p53 nuclear accumulation
and progesterone receptor positivity but not estrogen positivity in human female
breast cancer.
Faedo M, Ford CE, Mehta R, Blazek K, Rawlinson WD.
Clin Cancer Res. 2004 Jul 1;10(13):4417-9.
PMID: 15240531 Free Article

Duncan

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Karin, this is an awesome - and admittedly frightening  ??? - list.  Very sobering.

Karin

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The yellow fever vaccine was passaged in mouse brains then in eggs, and in the late sixties was shown widely contaminated with avian retroviruses. I don't see how it could not have been contaminated with mouse retroviruses as well, since the yellow fever virus was passaged in mouse brain hundreds of time as part of the initial attenuation process and nobody ever looked for those back then.

This vaccine was administered to ALL US recruits at the beginning of World War II and dozens of millions of Africans also had got it by then. I am in my car now but later I can post references if anyone wants, the above statements are published in the medical literature available in PubMed.

So just with the fact above, one can understand how murine retroviruses might have been injected in a very wide scale in the human population from the 1930's to at least the early 1970's. We are talking million and millions of people there.

Could this have anything to do with rise in cancer incidence since then, and who knows what else?
« Last Edit: February 17, 2012, 08:55:06 PM by Karin »

Karin

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The Yellow Fever Vaccine: A History
Yale J Biol Med. 2010 June; 83(2): 77–85
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892770/#R28

Some key points:

- The yellow fever vaccine was produced by attenuating the virus through passaging hundreds of times through mouse brain.

- The first human trial were done in the US in 1931 and in Tunis shortly after.

- By 1945, 16 millions of Africans had been immunized with this mouse-brain-derived vaccine.

- Vaccine side-effects included encephalitis and neurologic reactions. However, "surveillance for delayed reactions may not have been complete, and detailed follow-up statistics are not available."

- During WWII, the yellow fever vaccine was given to virtually all US recruits (7 million doses).

- In 1962 a seed lot of vaccine was found contaminated with avian leukosis viruses, which are endogenous retroviruses that infect and can lead to cancer in chickens and other animals. "Undoubtedly, thousands or millions of people had been inadvertently inoculated with these potentially oncogenic viruses."

subtr4ct

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Disclaimer: I am not a medical doctor.  This post is not medical advice.  Consult your physician before taking any action.

Dr. Yes

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Thanks Mr subtr4ct!

I can't go into this paper in depth but I wanted to mention a couple things.  I'm surprised that they used the single-round assay from the Erlwein/McClure study, rather than the quantitative or RT-PCR tissue assays used in a number of positive prostate cancer studies.  Yes, they were trying to avoid contamination, but the sensitivity of the assay became much lower as a result. 

Nevertheless, they did find 2 out of 12 prostate cancer samples to be positive, and were able to sequence one of them.  It was a small fragment from the gag region, and was about 98% identical to VP62 XMRV.  However, it did have three point mutations (one deletion and two substitutions), which suggests that this is not VP62 plasmid contamination and instead represents a genuine infection with XMRV. 

They mention that one of the possible alternative explanations for this sequence is a sequencing error (which they couldn't rule out because they didn't isolate enough of the viral DNA).  I suppose it might also be possible that the VP62 plasmids they obtained were not as genetically homogenous as advertised, and subsequently contaminated their experiment.

If they found a genuine human retroviral infection, it still may not necessarily be XMRV. The fragment they sequenced is from the gag region of the virus.  Lombardi et al reported finding gag sequences that were very close to VP62 but were unable to find XMRV env sequences, suggesting that the virus was not XMRV (but may be a recombinant of some kind).  If the WPI's gag PCR results were correct, then what Khan et al found may be similar, i.e. not XMRV in its entirety.

 
« Last Edit: February 19, 2012, 11:11:04 PM by Dr. Yes »
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jemal

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Thanks Dr. Yes. It's a shame they didn't have enough material to do further tests.

Patricia/Wildaisy

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http://okeefe-lab.blogspot.com/2012/02/evidence-for-xmrv-like-sequence-in.html

Wednesday, February 22, 2012   Evidence for an XMRV-like sequence in prostate cancer?    Just saw this one today, published in the British Journal of Cancer, a respectable journal-- despite the title of the paper, "No evidence for the involvement of XMRV or MCV in the pathogenesis of breast cancer.", the paper goes on to describe single-round PCR amplification of an XMRV type sequence in two cases of prostate cancer (out of 12).  They had optimized the reaction so as to detect 700 copies of purified plasmid DNA -- one sample did not elicit sufficient product to clone, but the other did, and upon sequencing it was the same as the VP62 sequence with two exceptions - indicating it is not likely to be contamination from the plasmid the investigators used as a control.  One caveat, the group does not appear to have tested the tissues for mouse DNA -- and they acknowledge this by admitting that the sequence could be from exogenous DNA.  If you have access to the journal, you can read the paper here.
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anciendaze

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By coincidence I added reference 43 (Johal 2010) on that list to the research archive today. 

currer

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What struck me, looking at the Wiki on polyomavirus, http://en.wikipedia.org/wiki/Polyomaviridae#Human_Polyomaviruses
is that seven new human polyomaviruses have been discovered since 2007, known to be tumor viruses, and accepted as human infections without controversy.

So why is there such resistance to new human retroviral infections? Is it because retroviruses are too fragile to infect as airborne diseases and require a blood borne vector of some sort? And this is where the resistance comes in? The fear that artificial interventions may be to blame?