MMTV Infectious Cycle and the Contribution of Virus-encoded Proteins to Transformation of Mammary Tissue

Department of Microbiology/Abramson Family Cancer Center, University of Pennsylvania, 421 Curie Blvd., Philadelphia, PA 1914, USA.
Journal of Mammary Gland Biology and Neoplasia (Impact Factor: 4.53). 09/2008; 13(3):299-307. DOI: 10.1007/s10911-008-9090-8
Source: PubMed


Mouse mammary tumor virus has served as a major model for the study of breast cancer since its discovery 1920's as a milk-transmitted agent. Much is known about in vivo infection by this virus, which initially occurs in lymphocytes that then carry virus to mammary tissue. In addition to the virion proteins, MMTV encodes a number of accessory proteins that facilitate high level in vivo infection. High level infection of lymphoid and mammary epithelial cells ensures efficient passage of virus to the next generation. Since MMTV causes mammary tumors by insertional activation of oncogenes, which is thought to be a stochastic process, mammary epithelial cell transformation is a by-product of the infectious cycle. The envelope protein may also participate in transformation. Although there have been several reports of a similar virus in human breast cancer, the existence of a human MTV has not been definitely established.

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    • "The transforming qualities of retroviruses have been appreciated for over a century [1]. Although the specific nature of mechanisms involved in retroviral infection was not appreciated until 1970 with the identification of reverse transcriptase, they had already been implicated in the initiation and promotion of many cancers in animals [1] [2]. Their role in human cancers has only begun to be appreciated in more recent years. "
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    ABSTRACT: Retroviral transformation has been associated with pro-proliferative oncogenic signaling in human cells. The current study demonstrates that transduction of human breast carcinoma cells (MDA-MB231) with LXSN and QCXIP retroviral vectors causes significant increases in growth rate, clonogenic fraction, and aldehyde dehydrogenase-1 positive cells (ALDH1+), which is associated with increased steady-state levels of cancer stem cell populations. Furthermore, this retroviral-induced enhancement of cancer cell growth in vitro was also accompanied by a significant increase in xenograft tumor growth rate in vivo. The retroviral induced increases in cancer cell growth rate were partially inhibited by treatment with 100 U/ml polyethylene glycol-conjugated-(PEG)-superoxide dismutase and/or PEG-catalase. These results show that retroviral infection of MDA-MB231 human breast cancer cells is capable of enhancing cell proliferation and cancer stem cell populations as well as suggesting that modulation of reactive oxygen species-induced pro-survival signaling pathways may be involved in these effects.
    06/2014; 2(1). DOI:10.1016/j.redox.2014.06.006
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    • "Endogenous Mtv maintain a genetic structure similar to their exogenous MMTV counterparts. For a detailed description of this genetic makeup see the review by Ross (13). Briefly, MMTV is a type B retrovirus of the Retroviridae family that contains a 9 kb RNA genome encoding virion capsid (Gag) proteins, reverse transcriptase and integrase enzymes necessary for viral replication (Pol), and envelope (Env) proteins used for viral entry. "
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    ABSTRACT: Mouse Mammary Tumor Viruses are beta-retroviruses that exist in both exogenous (MMTV) and endogenous (Mtv) forms. Exogenous MMTV is transmitted via the milk of lactating animals and is capable of inducing mammary gland tumors later in life. MMTV has provided a number of critical models for studying both viral infection as well as human breast cancer. In addition to the horizontally transmitted MMTV, most inbred mouse strains contain permanently integrated Mtv proviruses within their genome that are remnants of MMTV infection and vertically transmitted. Historically, Mtv have been appreciated for their role in shaping the T cell repertoire during thymic development via negative selection. In addition, more recent work has demonstrated a larger role for Mtv in modulating host immune responses due to its peripheral expression. The influence of Mtv on host response has been observed during experimental murine models of Polyomavirus- and ESb-induced lymphoma as well as Leishmania major and Plasmodium berghei ANKA infection. Decreased susceptibility to bacterial pathogens and virus-induced tumors has been observed among mice lacking all Mtv. We have also demonstrated a role for Mtv Sag in the expansion of regulatory T cells following chronic viral infection. The aim of this review is to summarize the latest research in the field regarding peripheral expression of Mtv with a particular focus on their role and influence on the immune system, infectious disease outcome, and potential involvement in tumor formation.
    Frontiers in Oncology 11/2013; 3:287. DOI:10.3389/fonc.2013.00287
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    • "The etiological role of retroviruses in mammary cancer of experimental animals coupled with observations of morphologically similar particles in human milk has motivated considerable interest in the biological role of these virions in human breast cancer. However, no correlation could be demonstrated between the presence of retrovirus-like particles in human milk samples and human breast cancer [19,20]. Thus, lacking formal proof of a human mammary tumor virus, the possibility that human breast cancer might also be intimately associated with oncogenic viruses faded in the 1980s [21]. "
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    ABSTRACT: Human milk samples contain microvesicles similar to the retroviruses. These microvesicles contain mRNA transcripts and possess reverse transcriptase activity. They contain about 14,000 transcripts representing the milk transcriptome. Microvesicles are also enriched with proteins related to “caveolar-mediated endocytosis signaling” pathway. It has recently been reported that microvesicles could be transferred to other cells by endocytosis and their RNA content can be translated and be functional in their new location. A significant percentage of the mammalian genome appears to be the product of reverse transcription, containing sequences whose characteristics point to RNA as a template precursor. These are mobile elements that move by way of transposition and are called retrotransposons. We thought that retrotransposons may stem from about 14,000 transcriptome of breast milk microvesicles, and reviewed the literature. The enhanced acceptance of maternal allografts in children who were breast-fed and tolerance to the maternal MHC antigens after breastfeeding may stem from RNAs of the breast milk microvesicles that can be taken up by the breastfed infant and receiving maternal genomic information. We conclude that milk microvesicles may transfer genetic signals from mother to neonate during breastfeeding. Moreover, transfer of wild type RNA from a healthy wet-nurse to the suckling neonate through the milk microvesicles and its subsequent reverse transcription and integration into the neonate genome could result in permanent correction of the clinical manifestations in genetic diseases.
    Theoretical Biology and Medical Modelling 06/2012; 9(1):20. DOI:10.1186/1742-4682-9-20 · 0.95 Impact Factor
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