Mouse mammary tumor virus and human breast cancer.
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Animals↗
Biomedical subjects
Christine Mant
Publications and source records attributed to Christine Mant.
Identification of HPV variants.
The vast majority of anogenital carcinomas are caused by high-risk human papillomaviruses (HPVs), and among Western nations HPV-16 is usually the most predominant cancer-associated type. As a DNA virus, HPV type 16 has a relatively stable genome that is believed to have co-evolved with its host over the millennia. Nevertheless, among the "wild" populations of HPV-16 that are circulating, a large number of variants have been identified, and these may have considerably different pathogenic potentials. In this chapter, methods for screening and characterizing HPV-16 sequence variants are described. In particular, we describe methods for the identification of variation within the HPV-16 E5 open reading frame and for the detection of the nt 131 A-->G mutation of the E6 ORF, using restriction fragment length polymorphism assays. In addition, we describe approaches for DNA sequencing and analysis. Such methods are likely to be of particular interest to those involved in epidemiological investigations of virus transmission and pathogenicity studies.
Base Sequence↗
Detection of HPV transcripts by nested RT-PCR.
Human papillomaviruses (HPVs) are etiologic for the development of cervical cancer and its precursor lesions, cervical intraepithelial neoplasia (CIN). Nearly all cervical carcinomas (CaCx) harbor HPV DNA, but the presence of HPV alone is not indicative of the future development of neoplasia. While both normal and abnormal smears may harbor HPV DNA, the detection of HPV mRNA is associated, although not exclusively, with abnormal cytology. Recent observations suggest women with a high HPV viral load are at a significantly greater risk for CIN development--particularly those infected with high-risk (HR) HPV types, such as HPV type 16 (HPV 16). Thus, assays capable of detecting HPV transcripts may have useful prognostic value and could be utilized to identify biological markers for progression to high-grade cervical disease. This chapter describes the nested reverse transcriptase (nRT)-polymerase chain reaction (PCR) methods developed in our laboratory for the detection of the majority of all early region HPV-16 transcripts.
Base Sequence↗
Human murine mammary tumour virus-like agents are genetically distinct from endogenous retroviruses and are not detectable in breast cancer cell lines or biopsies.
It has been reported that a human murine mammary tumour virus (MMTV)-like virus (HMLV), which may be an endogenous human retrovirus (HERV), occurs in the human breast cancer cell lines T47D and MCF-7 and, in 38% of human breast cancer biopsies. As the aetiology of most breast cancers remains unknown, it is important to verify these observations in differing breast cancer populations worldwide. Thus, we sought to determine the genetic relationships between HMLVs, MMTVs, and HERVs, and to investigate the association between HMLVs and breast cancer biopsies from South London, UK. Phylogenetic analyses of the env/pol region indicated that HMLVs are indistinct from MMTVs, and that MMTVS/HMLVs exhibit only low sequence homologies with HERVs. A search of the human genome confirmed that HMLVs are not endogenous. Using MMTV polymerase chain reaction (PCR) primers described previously, we amplified DNA from all cell lines except MCF-7 and from 7 of 44 (16%) breast cancer biopsies. A restriction fragment length polymorphism assay was designed to distinguish between HMLVs and MMTVs, and upon analyses, PCR amplicons appeared to be HMLVs. To confirm these findings, amplicons from the T47D cell line and from four randomly selected breast cancer patients were sequenced. Of 106 DNA sequences obtained, 103 were homologous with a short arm of human chromosome (Chr) 3 (3p13), two with Chr 4, and one with Chr 8. None of the sequences exhibited significant nucleotide homology with MMTVs, HMLVs, or with HERVs (all <50%). Thus, we conclude that (i) HMLVs are integral members of the MMTV family; (ii) MMTVs/HMLVs are genetically distinct from HERVs; (iii) MMTV/HMLV DNA is not present in human breast cancer cell lines or clinical biopsies in our locality.
Adult↗
A viral aetiology for breast cancer: time to re-examine the postulate.
Despite decades of research, no aetiologic factor(s) for human breast cancer has been identified and the search for a causal agent has all but been abandoned during the past thirty years. Over 60 years ago, it was demonstrated that breast tumours in mice are caused by an oncornavirus, murine mammary tumour virus (MMTV). Whilst many at that time postulated a similar virus might be the causative agent of human breast cancer, genetic evidence was difficult to obtain primarily because of the occurrence of endogenous human retrovirus (HER) sequences within the human genome that share extensive regions of nucleotide homology with MMTV. Recently, there has been a resurgence of interest in the possibility that a significant proportion of human breast cancers may be caused by viral infections. Two candidate viruses have been proposed, a human retroviral analogue of MMTV (which differs significantly in sequence and characteristics from HERs) and, the Epstein-Barr virus (gamma-herpes virus). These two viruses have been reported to occur in up to 37 and 50% of breast cancer cases, respectively. Here we present the background to the infectious hypothesis for the aetiology of breast cancer and review recent findings.
Breast Neoplasms↗
Buccal exposure to human papillomavirus type 16 is a common yet transitory event of childhood.
High-risk human papillomaviruses, such as type 16 (HPV-16), are established etiological agents for cervical carcinoma. In most cases, this virus is transmitted sexually, though can also be spread from mother to infant at delivery. We have demonstrated previously a high prevalence ( approximately 52%) of HPV-16 DNA in the mouths of prepubertal children, albeit with low levels of transcription [Rice et al., 2000]. We investigated whether childhood buccal infections with HPV-16 are persistent or transient and whether children became infected through contact with their immediate family members. Two groups of children were selected: one group were all initially HPV-16 E5 DNA-positive in sensitive polymerase chain reaction tests of swabs from their buccal mucosa (n = 20), and the other group consisted of children who were all HPV-16 E5-negative (n = 19). Thirty months later, a second oral swab was collected from each child and tested for HPV DNA. At this second visit, 40% of the HPV-16-positive group had no detectable HPV-16 DNA; conversely, 63% of children who were originally HPV-16-negative had now acquired the virus. Three months later, a third sample was collected from eight children and their immediate families (seven were HPV-16 E5 DNA-positive at the second visit). Amongst the family samples tested, in two families a single previously untested child was HPV-16 DNA-positive. It is concluded that HPV-16 DNA in the oral cavities of children is a transient event and is most probably acquired from their peers.
Case-Control Studies↗
A human murine mammary tumour virus-like agent is an unconvincing aetiological agent for human breast cancer.
There has recently been renewed interest in both the scientific literature, and in the media, that a human relative (HMLV) of murine mammary tumour virus (MMTV) may be implicated in the aetiology of up to 42% of sporadic cases of human breast cancer. Such reports are potentially of considerable clinical significance, as aside from the small percentage of genetically acquired breast cancers, the cause of sporadic cases of breast cancer is completely unknown. Indeed, convincing proof of an infectious cause for human breast malignancies would permit the development of new preventative measures, treatment modalities and raise the possibility of prophylactic and therapeutic vaccines. Here we review the historical background for a retroviral cause of human breast cancers and give an up-to-date critique of the most recent research findings. We conclude that the available evidence for an infectious aetiology of human breast cancers is unconvincing. Amongst the many cognate arguments against an infective hypothesis for sporadic cases of human breast cancer are the facts that: (i). human tissues lack the appropriate cell-surface receptor for entry of MMTVs/HMLVs; (ii). unlike all other virally caused human malignancies, immunodeficiency does not predispose to an increased incidence, or prevalence, of human breast cancers; and, (iii). reports of PCR amplification of MMTV/HMLV sequences from breast cancers have been robustly disputed by four independent laboratories. Indeed positive PCR results may be readily explained by the mis-amplification of host genomic DNA. Hence, the burden of proof currently lies with those who champion a viral cause for sporadic cases of breast cancer.
Animals↗