Rapid spread of mouse mammary tumor virus in cultured human breast cells

Indik, Stanislav; Günzburg, Walter H.; Kulich, Pavel; Salmons, Brian; Rouault, Francoise

doi:10.1186/1742-4690-4-73

Cited by 57 publications

(65 citation statements)

References 23 publications

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“…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 (8)(9)(10). Together, these data suggest a possible causal role for MMTV-like virus in some human breast cancers.…”

Section: Interpretation Of the Datasupporting

confidence: 87%

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Mouse Mammary Tumor Virus–like Sequences in Human Breast Cancer

et al. 2010

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Mouse mammary tumor virus (MMTV) sequences have been reported to be present in some human breast cancers, but it is unclear whether they have any causal role. In mice, MMTV promotes tumor formation indirectly by insertional mutagenesis of Wnt oncogenes that lead to their activation. In this study, we investigated the status of Wnt-1 in human breast cancers harboring MMTV-like sequences encoding viral envelope (env) genes. We confirmed the detection of env sequences in the nucleus of human breast cancer specimens that are similar in appearance to mouse mammary tumors expressing MMTV env sequences. MMTV env sequences in human breast cancers were also nearly indistinguishable from env sequences in mouse MMTV isolates. Further, Wnt-1 expression was higher in specimens of env-positive ductal carcinoma in situ and invasive ductal carcinoma, relative to env-negative specimens. Our findings extend the evidence that MMTV sequences found in naturally occurring mouse mammary tumors can be found in some human breast cancers, prompting further evaluation of causal roles in these settings. Cancer Res; 70(9); 3576-85. ©2010 AACR.

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Section: Interpretation Of the Datasupporting

confidence: 87%

“…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 (7). MMTV can infect, integrate, and multiply in human breast epithelial cancer cell lines (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Mouse Mammary Tumor Virus–like Sequences in Human Breast Cancer

et al. 2010

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“…Recent studies have also shown that XMRV infectivity can be limited by the presence of known host restriction factors to retroviral replication, such as the human APOBEC3 and tetherin proteins, as well as mouse APOBEC3, tetherin, and Fv1 proteins (11,28). It is noteworthy that a number of human cells, including breast cells have been shown to be susceptible to infection by the mouse mammary tumor virus (MMTV) (13,14), in spite of the fact that the human orthologue of the murine transferrin receptor 1 (Trf1), which is the known cellular receptor for MMTV, is not able to support viral entry in human cells (32). In a recent study, XMRV protein antigens have been detected mainly in malignant prostatic epithelial cells (23%) but only rarely in stromal cells (4%) of prostate cancer tissues collected from one institution (34).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Cellular Determinants Required for In Vitro Xenotropic Murine Leukemia Virus-Related Virus Entry into Human Prostate Cancer and Noncancerous Cells

Bhosle¹,

Suppiah²,

Molinaro³

et al. 2010

J Virol

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Prostate cancer is the most common male malignancy in Western countries and the second most common cause of cancer-related deaths in males worldwide (15,24). The known risk factors for prostate cancer are hormones (i.e., androgens), diet, sex, and race, as well as environmental and genetic factors (27). A recent study suggests that susceptibility to prostate cancer can be influenced by the genetic variations associated with an antagonistic coevolution, which occurs between a specific host locus (RNASEL), known to be involved in antiviral innate immune defense, and a viral pathogen (38). Indeed, several epidemiologic studies have supported the involvement of the RNASEL gene in the prostate cancer etiology (4,5,30,31), whereas other studies do not (9,22,34,43). Some studies have reported that individuals with a single mutated copy of the RNASEL gene have a 50% increased risk for prostate cancer, whereas those with homozygous mutant RNASEL alleles have a 2-fold-increased risk of prostate cancer (5).The RNASEL gene encodes for the RNase L protein, a constitutively expressed latent endoribonuclease, which mediates the interferon-inducible 2-5A system against viral and/or cellular double-stranded RNAs (8,16,20,23,49,50). The RNase L "Q" variant allele (R462Q) shows a 3-fold decrease in catalytic activity compared to the wild-type enzyme (5, 44). The possible association of mutant RNASEL alleles with human prostate cancers suggests an enhanced susceptibility of prostate tissues to a viral agent. This hypothesis has led to the recent identification of a new human retrovirus, xenotropic murine leukemia virus (MuLV)-related virus (XMRV), in 40% of prostate cancer patients with the QQ variant alleles of RNASEL compared to 1.5% among heterozygous (RQ) and wild-type (RR) RNASEL carriers (41). XMRV virus infection appears to be susceptible to inhibition by interferon and its downstream effector RNase L protein (7). However, a recent study has provided some evidence to show that XMRV infection is independent of the RNASEL genotype (34), suggesting that population differences and/or other environmental or genetic factors may influence the impact of RNASEL on prostate cancer development.The XMRV genome is 8,185 nucleotides in length and shares up to 95% overall nucleotide sequence identity with known xenotropic MuLVs (41). One receptor for xenotropic MuLVs is Xpr1, a 696-amino-acid protein with multiple transmembrane-spanning domains (2). Expression of this protein in Chinese hamster ovary (CHO) cells that are not known to express Xpr1 endogenously confers an enhanced susceptibility of these cells to xenotropic MuLV infection (2). Infection of hamster and mouse cells with XMRV-like virus that is derived from a prostate cancer cell line (22Rv1) also requires Xpr1 as a receptor (18). Earlier studies have demonstrated the importance of certain residues located within the putative third and fourth extracellular loops (ECL3 and ECL4) of Mus dunni's Xpr1 in conferring infection by xenotropic MuLVs (25). Furthermore, it has been shown ...

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“…Indeed, it has recently been reported (9) that inflammatory breast cancers from American women show a higher incidence of HMTV-related viral sequences (71%) than sporadic breast cancers, and that the presence of MMTV-env-like exogenous sequences is strictly related to tumor progression (10). Additional support for possible involvement of the virus in breast cancer comes from reports claiming that MMTV can infect and spread through a culture of human mammary cells (11,12); the MMTV env protein, through a specific sequence motif, can initiate changes that are consistent with transformation of mammary epithelial cells (13); cells isolated from ascites or pleural effusions of patients with metastatic breast cancer contained MMTV sequences in their DNA, expressed the MMTV Env protein and showed b-retroviral particles by electron microscopy, similar to the mouse virus (14). The same group recently reported detection of HMTV proteins in human breast cancer cells (15).…”

Section: Introductionmentioning

confidence: 99%

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

Feldman

Roniger

Bar-Sinai

et al. 2012

Molecular Cancer Research

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Mouse mammary tumor virus (MMTV) is associated primarily with mammary carcinomas and lymphomas. The signal peptide of the MMTV envelope precursor is uniquely targeted to nucleoli of cells that harbor the virus, where it can function as a nuclear export factor for intron-containing transcripts. Antibodies to this signal peptide, which we refer to as p14, were previously shown to label nucleoli in a subset of human breast cancers. To look for additional cellular functions of p14, different mutants were ectopically expressed in the MCF-7 human breast cancer cell line. This approach identified motifs responsible for its nucleolar targeting, nucleocytoplasmic shuttling, target protein (B23, nucleophosmin) binding, and phosphorylation at serine 18 and 65 both in situ and in vitro. To test the role of these phosphorylation sites, we carried out in vivo tumorigenesis studies in severe combined immunodeficient mice. The findings show that the p14-Ser65Ala mutation is associated with impaired tumorigenicity, whereas the p14-Ser18Ala mutation is associated with enhanced tumorigenicity. Microarray analysis suggests that phosphorylation at serine 18 or at serine 65 is associated with transcriptional regulation of the L5 nucleolar ribosomal protein (a p14 target) and the Erb-B signal transduction pathway. Taken together, these results show that the phosphorylation status of p14 determines whether it functions as a pro-oncogenic or antioncogenic modulator.

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Rapid spread of mouse mammary tumor virus in cultured human breast cells

Abstract: Taken together, our results show that human cells can support replication of mouse mammary tumor virus.

Cited by 57 publications

References 23 publications

Mouse Mammary Tumor Virus–like Sequences in Human Breast Cancer

Mouse Mammary Tumor Virus–like Sequences in Human Breast Cancer

Evaluation of Cellular Determinants Required for In Vitro Xenotropic Murine Leukemia Virus-Related Virus Entry into Human Prostate Cancer and Noncancerous Cells

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

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