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Aromatase and post-transcriptional regulation
Summary
This project is focussed on the characterisation of the post-transcriptional regulation of LRH-1 and SF-1 and its significance for aromatase expression.
Description
In women, cancers often arise in the oestrogen sensitive tissues of the breast, ovary and uterus. The key enzyme in oestrogen synthesis is aromatase and drugs that target it are successful therapeutics for breast cancer and have promise for endometrial cancer.
Recently, work in our laboratory , has identified the transcription factors LRH-1/NR5A1 and SF-1/NR5A2 as critical regulators of aromatase expression and these provide new avenues for the development of cancer therapies.
The significance of post-transcriptional regulation of LRH-1 and SF-1 is being examined in a model system of oestrogen synthesis, the granulosa cell tumour cell line, KGN. Recently it was demonstrated that many genes are regulated at the mRNA level by small non-coding RNAs, including micro-RNA (miRNA).
The gene structure of LRH-1 indicates that it is under such control and we are identifying miRNA species that influence LRH-1 expression and regulate aromatase. At the protein level, SF-1 and LRH-1 are known to subject by protein modifications including ubiquitinisation and sumoylation.
The functional significance of their sumoylation with respect to their regulation of aromatase is being characterised. Together, it is expected that these investigations will reveal new opportunities for the therapeutic regulation of oestrogen synthesis.
Funding
National Health and Medical Research Council