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Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification.

ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates gene transcription associated with intermediary metabolism, adipocyte differentiation, and tumor suppression and proliferation. To understand the role of PPARgamma in tumorigenesis, transgenic mice were generated with mammary gland-directed expression of the dominant-negative transgene Pax8PPARgamma. Transgenic mice were phenotypically indistinguishable from wild-type (WT) mice, but mammary epithelial cells expressed a greater percentage of CD29(hi)/CD24(neg), CK5(+), and double-positive CK14/CK18 cells. These changes correlated with reduced PTEN and increased Ras and extracellular signal-regulated kinase (ERK) and AKT activation. Although spontaneous tumorigenesis did not occur, transgenic animals were highly susceptible to progestin/7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis, which in contrast to WT mice resulted in a high tumor multiplicity and, most importantly, in the appearance of predominantly estrogen receptor alpha-positive (ER(+)) ductal adenocarcinomas. Tumors expressed a similar PTEN(lo)/pERK(hi)/pAKT(hi) phenotype as mammary epithelium and exhibited high activation of estrogen response element-dependent reporter gene activity. Tumorigenesis in MMTV-Pax8PPARgamma mice was insensitive to the chemopreventive effect of a PPARgamma agonist but was profoundly inhibited by the ER antagonist fulvestrant. These results reveal important new insights into the previously unrecognized role of PPARgamma in the specification of mammary lineage and the development of ER(+) tumors.

SUBMITTER: Yin Y

PROVIDER: S-EPMC3693579 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification.

Yin Yuzhi Y Yuan Hongyan H Zeng Xiao X Kopelovich Levy L Glazer Robert I RI

Cancer research 20090101 2

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates gene transcription associated with intermediary metabolism, adipocyte differentiation, and tumor suppression and proliferation. To understand the role of PPARgamma in tumorigenesis, transgenic mice were generated with mammary gland-directed expression of the dominant-negative transgene Pax8PPARgamma. Transgenic mice were phenotypically indistinguishable from wild-type (WT) mice, but mammary epitheli ...[more]

PMID: 19147585

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Project description:Apolipoprotein E (apoE) and its receptor, very low density lipoprotein receptor (VLDLR), are involved in fat accumulation in adipocytes. Here, we investigated the effect of a peroxisome proliferator-activated receptor (PPAR) gamma agonist, rosiglitazone, on regulation of VLDLR expression both in white adipose tissue (WAT) of obese mice and in cultured adipocytes. Furthermore, to determine whether rosiglitazone directly regulates transcription of the VLDLR gene, we carried out luciferase assay with a reporter gene containing mouse VLDLR promoter region, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Four-day treatment with rosiglitazone increased the expression of VLDLR in WAT of ob/ob mice. Moreover, rosiglitazone increased the expression of VLDLR in cultured adipocytes. The PPAR-responsive element (PPRE)-directed mutagenesis analyses revealed that the PPRE motif in the VLDLR promoter region plays a significant role in transcriptional activation of the VLDLR gene in adipocytes. In addition, electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that endogenous PPARgamma directly binds to this functional PPRE motif in the VLDLR promoter region. We also investigated the effects of rosiglitazone on insulin sensitivity and lipid accumulation in both ob/ob mice and apoE-deficient ob/ob mice. Rosiglitazone ameliorated insulin sensitivity in both ob/ob mice and apoE-deficient ob/ob mice, possibly through decreasing the expression of monocyte chemoattractant protein-1 (MCP-1), increasing the expression of superoxide dismutase 1 (SOD1) in WAT, and increasing plasma adiponectin concentration. In ob/ob mice, body weight and WAT weight were significantly higher in the mice treated with rosiglitazone than those treated with vehicle. However, in apoE-deficient ob/ob mice, no significant difference in body weight or WAT weight was observed between the vehicle-treated group and the rosiglitazone-treated group. Moreover, rosiglitazone did not increase body weight and WAT weight in VLDLR-deficient mice. These findings indicate that rosiglitazone directly increases VLDLR expression, thereby enhancing apoE-VLDLR-dependent lipid accumulation in adipocytes.

Dataset Information

Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification.

Publications

Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification.

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