Promoter switch: a novel mechanism causing biallelic PEG1/MEST expression in invasive breast cancer.
We have previously reported on the biallelic expression of the imprinted PEG1/MEST gene in infiltrating carcinomas of the breast. Putative loss of imprinting (LOI) of PEG1/MEST has subsequently also been implicated in the aetiology of lung adenocarcinomas and colon cancer. Taking advantage of our previous study, identifying seven infiltrating carcinomas of the breast, displaying biallelic PEG1/MEST expression, we have analysed the allelic usage of the two alternative PEG1/MEST transcripts encoding isoforms 1 and 2, separately. In addition, expression levels of the two transcripts have been measured by real-time RT-PCR, in order to elucidate the mechanism behind the switch from monoallelic transcription in normal breast tissue to biallelic expression in invasive cancer. The isoform 1 transcript is imprinted in both the paired normal tissue and the breast carcinomas. In contrast, the isoform 2 transcript is biallelically expressed, or in one case expressed from the opposite allele to isoform 1, raising the possibility that isoform 2 is polymorphically imprinted in normal breast tissue. In all the paired normal samples, isoform 1 is predominantly expressed, explaining the monoallelic profiles of these samples. However, in four of the seven biallelic carcinomas, isoform 2 is expressed at higher levels than isoform 1, indicating that a switch in expression from isoform 1 to isoform 2 is responsible for the biallelic profiles in these samples. Our results not only suggest a novel mechanism leading to biallelic expression detected when analysing the common 3'-UTR of the PEG1/MEST transcriptional unit, they are also indicative of the existence of further alternative PEG1/MEST transcripts.
Pedersen
Inge Søkilde
IS
Department of Pathology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Dervan
Peter
P
McGoldrick
Alo
A
Harrison
Michèle
M
Ponchel
Frederique
F
Speirs
Valerie
V
Isaacs
John D
JD
Gorey
Thomas
T
McCann
Amanda
A
D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D020033:Protein Isoforms; D011506:Proteins; C103637:mesoderm specific transcript protein