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Departments of ¹ Pathology and ² Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Cambridge, United Kingdom

Requests for reprints: Cathrine M. Holland, Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Box 223, Level 2, Robinson Way, Cambridge CB2 2SW, United Kingdom. Phone: 44-1223-336874; Fax: 44-1223-215327. E-mail: cath.holland{at}obgyn.cam.ac.uk

Endometrial cancer is the most common gynecologic malignancy, frequently arising in association with obesity and diabetes mellitus. To identify gene pathways contributing to endometrial cancer development, we studied the transcriptome of 20 endometrial cancers and 11 benign endometrial tissues using cDNA microarrays. Among the transcript changes identified in endometrial cancer were up-regulation of the nuclear hormone receptors peroxisome proliferator-activated receptors (PPAR) and , whereas retinoid X receptor ß was down-regulated. To clarify the contribution of PPAR to endometrial carcinogenesis, we did experiments on cultured endometrial carcinoma cells expressing this transcript. Treatment with fenofibrate, an activating ligand for PPAR, significantly reduced proliferation and increased cell death, suggesting that altered expression of nuclear hormone receptors involved with fatty acid metabolism leads to deregulated cellular proliferation and apoptosis. These results support further investigation of members of the PPAR/retinoid X receptor pathway as novel therapeutic targets in endometrial cancer.

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Received 3/30/04; revised 5/ 4/04; accepted 5/14/04.

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