Transcriptome analysis of endometrial cancer identifies peroxisome proliferator-activated receptors as potential therapeutic targets.
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) alpha and gamma, whereas retinoid X receptor beta was down-regulated. To clarify the contribution of PPARalpha to endometrial carcinogenesis, we did experiments on cultured endometrial carcinoma cells expressing this transcript. Treatment with fenofibrate, an activating ligand for PPARalpha, 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.
Department of Pathology, University of Cambridge, The Rosie Hospital, Box 223, Level 2, Robinson Way, Cambridge CB2 2SW, United Kingdom. cath.holland@obgyn.cam.ac.uk
Cathrine M
CM
Holland
Samir A
SA
Saidi
Amanda L
AL
Evans
Andrew M
AM
Sharkey
John A
JA
Latimer
Robin A F
RA
Crawford
D Stephen
DS
Charnock-Jones
Cristin G
CG
Print
Stephen K
SK
Smith
D016923:Cell Death; D002460:Cell Line; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000473:pathology; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018076:DNA, Complementary; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D012313:RNA