Journal
CLINICAL CANCER RESEARCH
Volume 13, Issue 1, Pages 246-252Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-06-1947
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Funding
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000034] Funding Source: NIH RePORTER
- NCRR NIH HHS [M01-RR00034] Funding Source: Medline
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Purpose: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a steroid nuclear receptor that is activated by natural compounds such as specific fatty acids and synthetic drugs such as thiazolidinedione antidiabetic agents. Expressed in normal and malignant mammary epithelial cells, activation of PPAR gamma is associated with antiproliferative effects on human breast cancer cells in preclinical studies. The purpose of this study was to test the hypothesis that PPAR gamma ligand therapy might inhibit tumor growth and progression in human breast cancer. Experimental Design: We conducted a pilot trial of short-term (2-6 weeks) treatment with the thiazolidinedione rosiglitazone in 38 women with early-stage (T-is-T-2, N0-1, M-0) breast cancer, administered between the time of diagnostic biopsy and definitive surgery. Results: Short-term treatment with rosiglitazone (8 mg/d) did not elicit significant effects on breast tumor cell proliferation using Ki67 expression as a measure of cell proliferation and surrogate marker of tumor growth and progression. In pretreatment tumors notable for nuclear expression of PPAR gamma by immunohistochemistry, down-regulation of nuclear PPAR gamma expression occurred following rosiglitazone administration (P = 0.005). No PPARG mutations were identified, and the incidence of P12A and H446H polymorphisms did not differ relative to U.S. controls (P = 0.5). Treatment with rosiglitazone resulted in increased serum adiponectin (P < 0.001), decreased insulin levels (P = 0.005), and increased insulin sensitivity (P = 0.004). Rosiglitazone was well tolerated without serious adverse events. Conclusion: Our data indicate that short-term rosiglitazone therapy in early-stage breast cancer patients leads to local and systemic effects on PPAR gamma signaling that may be relevant to breast cancer.
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