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[Cancer Research 64, 3162-3170, May 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Activation of Peroxisome Proliferator-Activated Receptor {delta} Stimulates the Proliferation of Human Breast and Prostate Cancer Cell Lines

Ruth L. Stephen1, Mattias C. U. Gustafsson1, Morag Jarvis1, Roger Tatoud1, Barry R. Marshall1, Deborah Knight1, Ewa Ehrenborg2, Adrian L. Harris3, C. Roland Wolf1 and Colin N. A. Palmer1

1 Biomedical Research Centre and Cancer Research United Kingdom Molecular Pharmacology Unit, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom; 2 Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden; and 3 Cancer Research United Kingdom Molecular Oncology Unit, Weatherall lnstitute of Molecular Medicine, John Radcliffe Hospital, Oxford, England, United Kingdom

The nuclear receptor peroxisome proliferator-activated receptor {delta} [PPAR{delta}/ß (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPAR{delta} by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPAR{delta} selective agonists. Activation of PPAR{delta} with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPAR{delta} agonist, GW501516. Conditional expression of PPAR{delta} in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPAR{delta} in the proliferative response to this drug. Activation of PPAR{delta} in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor {alpha} (VEGF{alpha}) and its receptor, FLT-1, thus, suggesting that PPAR{delta} may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGF{alpha} and FLT-1 in these cells. Our observations provide the first evidence that activation of PPAR{delta} can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPAR{delta} antagonists may be of therapeutic value in the treatment of breast and prostate cancer.




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Copyright © 2004 by the American Association for Cancer Research.