Characterisation of the tumour suppressor gene ZACin breast tissue

ZAC (also known as PLAGL1/LOT1) is a transcription factor gene located on chromosome 6q24, a region that is frequently deleted in solid tumours. ZAC is known to promote cell cycle arrest and apoptosis, and loss of expression has been observed in several different cancers including primary breast tumours and breast cancer cell lines. Due to its antiproliferative properties, the downregulation or loss of this gene would be expected to deregulate cell growth. ZAC has also been shown to act as a transcriptional coactivator of nuclear receptors, including oestrogen receptors which are important as prognostic indicators and therapeutic targets in breast cancer.

ZAC is maternally imprinted in most tissues. Its promoter is believed to be located within a differentially methylated CpG island, and it directs transcription exclusively from the unmethylated paternal allele. As this imprinted promoter has been shown to be hypermethylated in ovarian cancer and breast cancer cell lines, similar epigenetic changes may occur in primary breast tumours, and may contribute to altered cell cycle regulation and thus tumour growth. In some tissues, however, ZAC expression is biallelic. We are currently studying the mechanism underlying this tissue-specific phenomenon. A detailed understanding of the way in which the expression of imprinted and nonimprinted transcripts is regulated in normal breast tissue will be required in order to allow analysis of the epigenetic mechanism for ZAC inactivation in breast tumours.