Stem Cell Antigen-1 Deficiency Enhances the Chemopreventive Effect of Peroxisome Proliferator-Activated Receptor gamma Activation

Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA..
Cancer Prevention Research (Impact Factor: 4.44). 09/2011; 5(1):51-60. DOI: 10.1158/1940-6207.CAPR-11-0256
Source: PubMed


Stem cell antigen-1 (Sca-1, Ly6A) is a glycerophosphatidylinositol (GPI)-anchored protein that was identified as a murine marker of bone marrow stem cells. Although Sca-1 is widely used to enrich for stem and progenitor cells in various tissues, little is known about its function and associated signaling pathways in normal and malignant cells. Here, we report that the absence of Sca-1 in the mammary gland resulted in higher levels of PPARγ and PTEN, and a reduction of pSer84PPARγ, pERK1/2, and PPARδ. This phenotype correlated with markedly increased sensitivity of Sca-1 null mice to PPARγ agonist GW7845 and insensitivity to PPARδ agonist GW501516. Reduction of Sca-1 expression in mammary tumor cells by RNA interference resulted in a phenotype similar to the Sca-1 deficient mammary gland, as evidenced by increased PPARγ expression and transcriptional activity, resulting in part from a lesser susceptibility to proteasomal degradation. These data implicate Sca-1 as a negative regulator of the tumor suppressor effects of PPARγ.

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Available from: Yuzhi Yin, Jul 28, 2014
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    • "PPARG was shown to regulate the expression of genes involved in triacylglyceride synthesis (LPIN1), fatty acids synthesis (ACACA, FASN, SREBF1), metabolism (SCD), and import (CD36) in bovine mammary epithelial cells (Kadegowda et al. 2009). Furthermore, several studies have shown that PPARG regulates signaling pathways, controlling and improving insulin sensitivity, cell proliferation, fatty acid β-oxidation, glucose utilization, adipocytes differentiation, and improves HSC maintenance (Ito et al. 2012; Yuan et al. 2012). "
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    ABSTRACT: Bovine mammary stem cells (MaSC) are a source of ductal and lobulo-alveolar tissue during the development of the mammary gland and its remodeling in repeating lactation cycles. We hypothesize that the number of MaSC, their molecular properties, and interactions with their niche may be essential in order to determine the mammogenic potential in heifers. To verify this hypothesis, we compared the number of MaSC and the transcriptomic profile in the mammary tissue of 20-month-old, non-pregnant dairy (Holstein-Friesian, HF) and beef (Limousin, LM) heifers. For the identification and quantification of putative stem/progenitor cells in mammary tissue sections, scanning cytometry was used with a combination of MaSC molecular markers: stem cell antigen-1 (Sca-1) and fibronectin type III domain containing 3B (FNDC3B) protein. Cytometric analysis revealed a significantly higher number of Sca-1(pos)FNDC3B(pos) cells in HF (2.94 ± 0.35 %) than in LM (1.72 ± 0.20 %) heifers. In HF heifers, a higher expression of intramammary hormones, growth factors, cytokines, chemokines, and transcription regulators was observed. The model of mammary microenvironment favorable for MaSC was associated with the regulation of genes involved in MaSC maintenance, self-renewal, proliferation, migration, differentiation, mammary tissue remodeling, angiogenesis, regulation of adipocyte differentiation, lipid metabolism, and steroid and insulin signaling. In conclusion, the mammogenic potential in postpubertal dairy heifers is facilitated by a higher number of MaSC and up-regulation of mammary auto- and paracrine factors representing the MaSC niche.
    Full-text · Article · Apr 2014 · Journal of applied genetics
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    • "Their tumor outgrowth data indicate that repression of Sca-1 reduces tumorigenicity or outgrowth potential as observed in normal mammary epithelial cells. Similarly, another report shows delayed tumor development in MP/DMBA induced tumors in Sca-1 knock-out mice [27]. In this case, the delay in tumor development was attributed to the upregulation and activation of PPARγ. "
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    ABSTRACT: Stem cell antigen-1 (Sca-1 or Ly6A) is a glycosyl phostidylinositol (GPI)-anchored cell surface protein associated with both stem and progenitor activity, as well as tumor initiating-potential. However, at present the functional role for Sca-1 is poorly defined. To investigate the role of Sca-1 in mammary tumorigenesis, we used a mammary cell line derived from a MMTV-Wnt1 mouse mammary tumor that expresses high levels of endogenous Sca-1. Using shRNA knockdown, we demonstrate that Sca-1 expression controls cell proliferation during early tumor progression in mice. Functional limiting dilution transplantations into recipient mice demonstrate that repression of Sca-1 increases the population of tumor propagating cells. In scratch monolayer assays, Sca-1 enhances cell migration. In addition, knockdown of Sca-1 was shown to affect cell adhesion to a number of different extracellular matrix components. Microarray analysis indicates that repression of Sca-1 leads to changes in expression of genes involved in proliferation, cell migration, immune response and cell organization. Sca-1 exerts marked effects on cellular activity and tumorgenicity both in vitro and in vivo. A better understanding of Sca-1 function may provide insight into the broader role of GPI-anchored cell surface proteins in cancer.
    Full-text · Article · Nov 2011 · PLoS ONE
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    ABSTRACT: The peroxisome proliferator-activated receptorγ (PPARγ) is a key regulator of metabolism, proliferation, inflammation and differentiation, and upregulates tumor suppressor genes, such as PTEN, BRCA1 and PPARγ itself. Examination of mammary carcinogenesis in transgenic mice expressing the dominant-negative Pax8PPARγ fusion protein revealed that tumors were estrogen receptorα (ER)-positive and sensitive to the ER antagonist, fulvestrant. Here we evaluated whether administration of an irreversible PPARγ 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 PPARγ inhibition, including PPARγ 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 PPARγ inhibitor can mimic a dominant-negative PPARγ 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.
    Full-text · Article · Apr 2012 · Oncotarget
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