Human mouse mammary tumor virus like elements and their relations to breast cancer
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
The human genome contains a variety of more or less ancient endogenous retroviral sequences. They are commonly referred to as HERVs (human endogenous retroviruses). Of all the known HERV groups, the HERV-K supergroup apparently comes closest to encoding functional retroviral proteins, although infectious particles have not been demonstrated. HERV-K may also be involved in human disease, including in tumour development. Mostgroups of HERV-K elements integrated into the germ line of Old World primates after the evolutionary separation from the New World primates. At least six groups of HML (human MMTV like) sequences have been identified by RT-PCR They have a nucleotide sequence dissimilarity of approximately 25% in the RT region. All seem to fall into the HERV-K supergroup.
We first used RT-PCR and dot blotting under group-specific conditions to study the RNA expression of HML in human malignant and nonmalignant breast tissue, placenta, and human normal peripheral blood mononuclear cells. We found a high expression of an HML-6 transcript in one of 60 breast cancer patients. The PCR product from this patient was cloned and sequenced. One sequence dominated and was named HML-6.2BC1. All other malignant breast samples gave a similar HML group expression pattern as the normal breast samples. Inplacenta, most of the 5 HML studied groups were highly expressed relative to the other tissues. A differential expression of HML was also found in peripheral blood mononuclear cells of 10 individuals.
To further characterize HML-6 sequences, we screened a human genomic library by using the HML-6.3 clone as probe. Three clones (HML-6.17, HML-6.28 and HML-6.29) were identified and fully sequenced, which revealed a sequence similar to type A, B and D retroviruses and belonging to the HERV-K family. The HML-6.28 element was a special case because the clone HML-6.2 BC1 identified it and it was 99% identical to HML-6.2BC1. We found that the HML-6.28 element is integrated into human chromosome 6, band p21-22. A mechanism for the possible causal involvement of HML-6.28 in the cancer cannot be inferred from our data.
By using inverse PCR (IPCR), we have investigated the integration pattern of HML sequences. Six integrations were studied in humans and primates. The results show large differences in mutational rate for the six integrations and favour that HML-6 sequences inserted into the germ line of human ancestors more than 20-30 million years ago.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1999. , 50 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 834
Medical sciences, human MMTV like sequence (HML), human breast cancer, expression of HML, integration of HML sequence, localization of HML-6
MEDICIN OCH VÅRD
Medical and Health Sciences
Research subject Microbiology
IdentifiersURN: urn:nbn:se:uu:diva-313ISBN: 91-554-4437-7OAI: oai:DiVA.org:uu-313DiVA: diva2:162228
1999-05-17, lecture hall at Dag Hammarskjölds väg 17, Uppsala, Uppsala, 13:00