The nuclear receptor peroxisome proliferator-activated receptor d [PPARd/ß (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARd by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARd selective agonists. Activation of PPARd 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 PPARd agonist, GW501516. Conditional expression of PPARd in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARd in the proliferative response to this drug. Activation of PPARd in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor a (VEGFa) and its receptor, FLT-1, thus, suggesting that PPARd 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 VEGFa and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARd can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARd antagonists may be of therapeutic value in the treatment of breast and prostate cancer.
Stephen, R. L., Gustafsson, M. C. U., Jarvis, M., Tatoud, R., Marshall, B. R., Knight, D., Ehrenborg, E., Harris, A. L., Wolf, C. R., & Palmer, C. N. A. (2004). Activation of peroxisome proliferator-activated receptor δ stimulates the proliferation of human breast and prostate cancer cell lines. Cancer Research, 64(9), 3162-3170. https://doi.org/10.1158/0008-5472.CAN-03-2760