Inhibition of Peroxisome Proliferator-Activated Receptor Increases Estrogen Receptor-Dependent Tumor Specification
Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia 20007, USA. Cancer Research
(Impact Factor: 9.33).
02/2009; 69(2):687-94. DOI: 10.1158/0008-5472.CAN-08-2446
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.
Available from: Shioko Kimura
- "Several in vitro studies demonstrated that PPFP has oncogenic activity such as increased cell cycle transition, reduced apoptosis, and enhanced growth , which is partly due to PPFP's dominant negative activity to suppress wild-type transcriptional activities of PPARγ [65, 71, 72], the suggested tumor suppressor [73, 74]. PPFP can also work as a dominant negative inhibitor of wild-type PPARγ in vivo . Further studies are required to establish the mechanisms for the PPFP-mediated tumorigenesis. "
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ABSTRACT: Homeodomain, forkhead domain, and paired domain-containing transcription factors play a major role in development, tissue-specific gene expression, and tissue homeostasis in organs where they are expressed. Recently, their roles in stem cell and cancer biology are emerging. In the thyroid, NKX2-1, FOXE1, and PAX8 transcription factors are responsible for thyroid organogenesis and expression of thyroid-specific genes critical for thyroid hormone synthesis. In contrast to their known roles in gene regulation, thyroid development and homeostasis, their involvement in stem cell, and/or cancer biology are still elusive. In order to further understand the nature of thyroid cancer, it is critical to determine their roles in thyroid cancer.
Journal of Thyroid Research 04/2011; 2011(1):710213. DOI:10.4061/2011/710213
Available from: Claire B Pollock
- "Stomach and tumors were excised, and formalin-fixed, paraffin-embedded sections were prepared for H&E staining and IHC. Antigen retrieval was carried out by incubation of tissue sections in 10 mM sodium citrate buffer (pH 6.0) for 20 min at a subboiling temperature in an electric steamer as previously described [19, 39]. Endogenous peroxidase activity was quenched with 3% hydrogen peroxide for 10 min and incubated for 30 min with blocking solution (10% goat serum in Tris-buffered saline), followed by incubation overnight at 4°C with the appropriate primary antibody diluted in blocking solution. "
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ABSTRACT: Peroxisome proliferator-activated receptorδ (PPARδ) regulates a multiplicity of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes likely create risk factors associated with the ability of PPARδ agonists to promote tumorigenesis in some organs. In the present study, we describe a new gastric tumor mouse model that is dependent on the potent and highly selective PPARδ agonist GW501516 following carcinogen administration. The progression of gastric tumorigenesis was rapid as determined by magnetic resonance imaging and resulted in highly metastatic squamous cell carcinomas of the forestomach within two months. Tumorigenesis was associated with gene expression signatures indicative of cell adhesion, invasion, inflammation, and metabolism. Increased PPARδ expression in tumors correlated with increased PDK1, Akt, β-catenin, and S100A9 expression. The rapid development of metastatic gastric tumors in this model will be useful for evaluating preventive and therapeutic interventions in this disease.
PPAR Research 12/2010; 2010(1):571783. DOI:10.1155/2010/571783 · 1.64 Impact Factor
Available from: Stefan K G Grebe
- "In summary, PPFP can act as a dominant negative inhibitor of wild-type PPAR␥ action both in vitro (Au et al., 2006; Espadinha et al., 2007; Gregory Powell et al., 2004; Kroll et al., 2000) and in vivo (Yin et al., 2009). PPFP is also capable of both stimulating and inhibiting selected PAX8-responsive genes (Espadinha et al., 2007). "
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ABSTRACT: When identified at early stages, most well-differentiated thyroid cancers are readily treated and yield excellent outcomes. Follicular thyroid cancer (FTC) however, when diagnosed at a late stage, may be very resistant to treatment, and exhibits 10-year survival rates less than 40%. Despite substantial progress in recent years, we still have limited understanding of the molecular and biological interrelationships between the various subtypes of benign and malignant follicular thyroid neoplasms. In contrast to the wealth of information available regarding papillary thyroid carcinoma (PTC), the triggering mechanisms of FTC development and the major underlying genetic alterations leading to follicular thyroid carcinogenesis remain obscure. Recent studies have focused on a chromosomal translocation, t(2;3) (q13;p25), fusing PAX8, a transcription factor that is essential for normal thyroid gland development, with the peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the steroid/thyroid nuclear receptor family. This chromatin rearrangement results in the expression of a PAX8/PPARgamma fusion protein, designated PPFP, whose incidence is relatively common in FTC and may represent an initiating event in the genesis of FTC. Here we review progress on the studies of PPFP that assess its involvement in FTC tumorigenesis.
Molecular and Cellular Endocrinology 10/2009; 321(1):50-6. DOI:10.1016/j.mce.2009.10.013 · 4.41 Impact Factor
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