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Inhibition of Proliferation and Estrogen Receptor Signaling by Peroxisome Proliferator-activated Receptor Ligands in Uterine Leiomyoma¹

University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957 [K. D. H., S. M. F., C. L. W.]; Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555 [J. A. C.]; Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [R. R. B.]; and Bristol-Myers Squibb, Endocrine Oncology Pharmaceutical Research Institute, Princeton, New Jersey 08543 [M. M. G.]

Peroxisome proliferator-activated receptor (PPAR) is an important signaling molecule in cells of mesenchymal origin, inducing differentiation and regulating cell proliferation in several cell types such as vascular smooth muscle cells. Leiomyomas arise from smooth muscle cells of the uterine myometrium with an incidence rate as high as 70% in women of reproductive age. PPAR signaling has not been characterized in these tumors, although prostaglandins, natural PPAR ligands, are known effectors of key biological functions in the normal myometrium. Leiomyomas and tumor-derived cells isolated from a rat model for this disease were characterized by Western analysis and found to express all three PPAR isoforms, suggesting that signaling pathways mediated by these receptors were intact in this tumor type. In vitro experiments with a leiomyoma-derived cell line demonstrated that the pan-PPAR ligand cis-4,7,10,13,16,19-docosahexaenoic acid and PPAR-specific ligands 15-deoxy-^12,14-prostaglandin J₂, troglitazone, and ciglitazone inhibited 17ß-estradiol-stimulated cell proliferation. This inhibitory effect was not observed with PPAR- or PPARß-specific ligands. Although both PPAR and estrogen receptor (ER) signaling pathways were intact in leiomyoma cells, in addition to growth inhibition, stimulation of PPAR signaling also inhibited ER-mediated gene expression. Human leiomyomas were also found to express all three PPAR isoforms, and primary cultures of these cells were sensitive to the inhibitory effects of PPAR ligands. These results suggest that in uterine leiomyomas PPAR activation is growth inhibitory and that this inhibition is mediated at least in part by negative cross-talk between ER and PPAR signaling pathways.

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