Drug-targeted inhibition of peroxisome proliferator-activated receptor-gamma enhances the chemopreventive effect of anti-estrogen therapy.
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ABSTRACT: The peroxisome proliferator-activated receptor? (PPAR?) is a key regulator of metabolism, proliferation, inflammation and differentiation, and upregulates tumor suppressor genes, such as PTEN, BRCA1 and PPAR? itself. Examination of mammary carcinogenesis in transgenic mice expressing the dominant-negative Pax8PPAR? fusion protein revealed that tumors were estrogen receptor? (ER)-positive and sensitive to the ER antagonist, fulvestrant. Here we evaluated whether administration of an irreversible PPAR? inhibitor in vivo could similarly induce ER expression in otherwise ER-negative mammary tumors following induction of carcinogenesis, and sensitize them to the antitumor effects of fulvestrant. In addition, we wished to determine whether the effect of GW9662 was associated with a PPAR-selective gene expression profile. Mammary carcinogenesis was induced in wild-type FVB mice by treatment with medroxyprogesterone and dimethylbenz(a)anthracene (DMBA) that were subsequently maintained on a diet supplemented with 0.1% GW9662, and tumorigenesis and gene expression profiling of the resulting tumors were determined. Administration of GW9962 resulted in ER+ tumors that were highly sensitive to fulvestrant. Tumors from GW9662-treated animals exhibited reduced expression of a metabolic gene profile indicative of PPAR? inhibition, including PPAR? itself. Additionally, GW9662 upregulated the expression of several genes associated with the transcription, processing, splicing and translation of RNA. This study is the first to show that an irreversible PPAR? inhibitor can mimic a dominant-negative PPAR? transgene to elicit the development of ER-responsive tumors. These findings suggest that it may be possible to pharmacologically influence the responsiveness of tumors to anti-estrogen therapy.
SUBMITTER: Yuan H
PROVIDER: S-EPMC3359890 | biostudies-literature | 2012 Mar
REPOSITORIES: biostudies-literature
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