Detection of MMTV-like LTR and LTR-env gene sequences in human breast cancer

Wang, Yue; Pelisson, Isabelle; Melana, Stella M.; Holland, James F.; Pogo, Beatríz G. T.

doi:10.3892/ijo.18.5.1041

Cited by 99 publications

(167 citation statements)

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“…Although this is the first report demonstrating evidence for betaretrovirus infection in patients with PBC, our findings are concordant with other investigators who have provided immunochemical, serologic, molecular hybridization and electron microscopy evidence of a human betaretrovirus infection in patients with breast cancer and healthy subjects (13,18,(25)(26)(27)(28). Full-length proviral betaretroviral sequences have been cloned from one PBC patients' peri-portal lymph node and two human breast cancer samples and fluorescent in situ hybridization studies have shown betaretrovirus integration in human chromosomes from metastatic breast cancer cells (ref.…”

Section: Discussionsupporting

confidence: 81%

“…These studies do not directly address a causal relationship between microbe and disease but they support the numerous reports documenting the presence of a betaretrovirus infection in humans (13,18,(25)(26)(27)(28). In this regard, we have devised a coculture model that can be used to test Koch's postulates in vitro by using either pure isolates or transfected DNA of the human betaretrovirus.…”

Section: Discussionmentioning

confidence: 69%

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Does a betaretrovirus infection trigger primary biliary cirrhosis?

Shen

Guo

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

217

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Patients with primary biliary cirrhosis develop progressive ductopenia associated with the production of antimitochondrial antibodies that react with a protein aberrantly expressed on biliary epithelial cells and peri-hepatic lymph nodes. Although no specific microbe has been identified, it is thought that an infectious agent triggers this autoimmune liver disease in genetically predisposed individuals. Previous serologic studies have provided evidence to suggest a viral association with primary biliary cirrhosis. Here we describe the identification of viral particles in biliary epithelium by electron microscopy and the cloning of exogenous retroviral nucleotide sequences from patients with primary biliary cirrhosis. The putative agent is referred to as the human betaretrovirus because it shares close homology with the murine mammary tumor virus and a human retrovirus cloned from breast cancer tissue. In vivo, we have found that the majority of patients with primary biliary cirrhosis have both RT-PCR and immunohistochemistry evidence of human betaretrovirus infection in lymph nodes. Moreover, the viral proteins colocalize to cells demonstrating aberrant autoantigen expression. In vitro, we have found that lymph node homogenates from patients with primary biliary cirrhosis can induce autoantigen expression in normal biliary epithelial cells in coculture. Normal biliary epithelial cells also develop the phenotypic manifestation of primary biliary cirrhosis when cocultivated in serial passage with supernatants containing the human betaretrovirus or the murine mammary tumor virus, providing a model to test Koch's postulates in vitro.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 69%

Does a betaretrovirus infection trigger primary biliary cirrhosis?

Shen

Guo

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

217

246

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“…DNA from breast tumors and lymphomas of 12 patients suffering from both malignancies was screened using PCR with primers specific for a 250-bp region of the MMTV ENV gene and primers specific for a 630-bp region within the MMTV LTR open reading frame (ORF) that codes for the MMTV superantigen (sag) gene (30 -32). Primer sequences used for these amplifications are specific for the MMTV ENV and LTR genes and are not found in any human endogenous retroviral sequences such as the human endogenous retroviral sequence-Ks (HERV-Ks) (13,15,20,22,23). Table 1 describes the malignancies of each of the 12 patients whose tissues were analyzed for MMTV-like ENV and LTR sequences and the ages at which their two malignancies were diagnosed.…”

Section: Resultsmentioning

confidence: 99%

“…PCR conditions for amplification of MMTV LTR sequences were the same as for envelope with the exception that MgCl 2 concentration was at 3.5 mmol/L. Primers (LTR 3 and LTR 5) and cycling conditions were those of Wang et al (20). To detect possible contamination of master mix components, a reaction without template DNA was routinely tested.…”

Section: Methodsmentioning

confidence: 99%

“…PCR products were hybridized on Southern blots (21) under stringent hybridization conditions to either a 23-bp probe specific for DNA sequences present in exogenous MMTV ENV sequences but not present in endogenous human endogenous retroviral sequence (HERV-K) DNA (13,15,22,23) or to a 20-bp probe specific for the MMTV LTR and also not present in endogenous human endogenous retroviral sequence (HERV-K) DNA (20,22,23). The 23-bp ENV probe, which extended from position 7822-7845 in the MMTV genome, and the 20-bp LTR probe, which extended from position 972-991 or 9545-9564 in the MMTV genome (24), were 5Ј end-labeled with [ 32 P]ATP using the RTS T4 kinase labeling kit (Life Technologies, Inc., Rockville, MD).…”

Section: Methodsmentioning

confidence: 99%

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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

Stewart

Dorai

et al. 2004

Clinical Cancer Research

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Purpose: In a previous study, we had detected the presence of mouse mammary tumor virus (MMTV)-like envelope (ENV) gene sequences in both the breast tumors and non-Hodgkin's lymphoma tissue of two of our breast tumor patients who had been diagnosed simultaneously with both malignancies. The aim of this study was to determine if MMTV-like DNA sequences are present in the breast tumors and non-Hodgkin's lymphomas of additional patients suffering from both malignancies and if so to characterize these sequences in detail.Experimental Design: DNA was extracted from formalinfixed, paraffin-embedded tissue sample blocks of breast tumors and non-Hodgkin's lymphomas from patients suffering from both malignancies. A 250-bp region of the MMTV ENV gene and a 630-bp region of the MMTV long terminal repeat (LTR) open reading frame (ORF) that encodes the MMTV superantigen (sag) gene were amplified by PCR from the isolated DNA. Amplified products were analyzed by Southern blotting, cloned, and sequenced.Results: MMTV-like ENV and LTR sequences were detected in both the breast tumors and non-Hodgkin's lymphomas of 6 of 12 patients suffering from both malignancies. A novel mutant of the MMTV ENV gene was identified in these patients. Characterization of the MMTV-like LTR highly variable sag sequences revealed total or nearly total identity to three distinct MMTV proviruses from two different branches of the MMTV phylogenetic tree.Conclusions: The presence of MMTV-like ENV and LTR sequences in both the breast tumors and nonHodgkin's lymphomas of 6 additional patients suggests a possible involvement of these sequences in these two malignancies. MMTV-like LTR sequence homology to different MMTV proviruses revealed the presence of more than one strain of MMTV-like sequences in each individual suggesting the possibility of multiple infections in these patients.

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Breaking tolerance to a tumor-associated viral superantigen as a basis for graft-versus-leukemia reactivity

et al. 2000

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A major goal in tumor immunotherapy consists of breaking potential tumor‐specific T‐cell unresponsiveness (tolerance), which may explain tumor growth in cancer patients. We report that immunological tolerance to a tumor‐associated viral superantigen (SAg) is overcome in a mouse lymphoma model by transfer of allogeneic T cells expressing SAg‐reactive Vβ6 T‐cell receptor chains. Surprisingly, upon contact with SAg‐expressing lymphoma cells, Vβ6 T cells became activated rather than tolerized (as reported previously). They also developed SAg‐specific cytotoxic T‐lymphocyte activity and secreted IL‐2 and IFN‐γ. The grafted T cells infiltrated liver metastases, formed close contact with SAg‐expressing tumor cells, and caused significant graft‐vs.‐leukemia (GvL) effects. Selection for tumor resistance among the progeny from a cross between SAg‐negative donor and SAg‐ positive recipient strains revealed a strict correlation between loss of the endogenous SAg tolerogen, rescue of Vβ6 T cells from SAg‐mediated deletion, and leukemia resistance. These findings suggest that immune responses to SAg can be exploited to break tolerance and augment immune responses to tumors. Int. J. Cancer 87:695–706, 2000. © 2000 Wiley‐Liss, Inc.

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Detection of MMTV-like LTR and LTR-env gene sequences in human breast cancer

Cited by 99 publications

References 0 publications

Does a betaretrovirus infection trigger primary biliary cirrhosis?

Does a betaretrovirus infection trigger primary biliary cirrhosis?

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

Breaking tolerance to a tumor-associated viral superantigen as a basis for graft-versus-leukemia reactivity

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