PPARδ Induces Estrogen Receptor-Positive Mammary Neoplasia through an Inflammatory and Metabolic Phenotype Linked to mTOR Activation

被引:44
作者
Yuan, Hongyan [1 ,2 ]
Lu, Jin [1 ,2 ]
Xiao, Junfeng [1 ,2 ]
Upadhyay, Geeta [1 ,2 ]
Umans, Rachel [7 ]
Kallakury, Bhaskar [3 ]
Yin, Yuhzi [4 ]
Fant, Michael E. [6 ]
Kopelovich, Levy [5 ]
Glazer, Robert I. [1 ,2 ]
机构
[1] Georgetown Univ, Dept Oncol, Washington, DC 20007 USA
[2] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA
[3] Georgetown Univ, Dept Pathol, Washington, DC 20007 USA
[4] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA
[5] NCI, Chemoprevent Agent Dev & Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA
[6] Univ S Florida, Dept Pediat, Tampa, FL 33620 USA
[7] Univ Chicago, Chicago, IL 60637 USA
关键词
GENE-EXPRESSION; FATTY-ACIDS; BREAST-CANCER; BETA/DELTA AGONIST; SIGNALING PATHWAY; MAMMALIAN TARGET; SKELETAL-MUSCLE; TRANSGENIC MICE; BETA; GROWTH;
D O I
10.1158/0008-5472.CAN-13-0322
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The peroxisome proliferator-activated receptor-delta (PPAR delta) regulates a multitude of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes are potential risk factors for the ability of PPAR delta agonists to promote tumorigenesis in the mammary gland. In this study, we describe a new transgenic mouse model in which activation of PPAR delta in the mammary epithelium by endogenous or synthetic ligands resulted in progressive histopathologic changes that culminated in the appearance of estrogen receptor-and progesterone receptor-positive and ErbB2-negative infiltrating ductal carcinomas. Multiparous mice presented with mammary carcinomas after a latency of 12 months, and administration of the PPAR delta ligand GW501516 reduced tumor latency to 5 months. Histopathologic changes occurred concurrently with an increase in an inflammatory, invasive, metabolic, and proliferative gene signature, including expression of the trophoblast gene, Plac1, beginning 1 week after GW501516 treatment, and remained elevated throughout tumorigenesis. The appearance of malignant changes correlated with a pronounced increase in phosphatidylcholine and lysophosphatidic acid metabolites, which coincided with activation of Akt and mTOR signaling that were attenuated by treatment with the mTOR inhibitor everolimus. Our findings are the first to show a direct role of PPARd in the pathogenesis of mammary tumorigenesis, and suggest a rationale for therapeutic approaches to prevent and treat this disease. (C) 2013 AACR.
引用
收藏
页码:4349 / 4361
页数:13
相关论文
共 87 条
[1]   Transcriptional network governing the angiogenic, switch in human pancreatic cancer [J].
Abdollahi, Amir ;
Schwager, Christian ;
Kleeff, Joerg ;
Esposito, Irene ;
Domhan, Sophie ;
Peschke, Peter ;
Hauser, Kai ;
Hahnfeldt, Philip ;
Hlatky, Lynn ;
Debus, Juergen ;
Peters, Jeffrey M. ;
Friess, Helmut ;
Folkman, Judah ;
Huber, Peter E. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (31) :12890-12895
[2]   Delayed mammary gland involution in MMTV-AKT1 transgenic mice [J].
Ackler, S ;
Ahmad, S ;
Tobias, C ;
Johnson, MD ;
Glazer, RI .
ONCOGENE, 2002, 21 (02) :198-206
[3]   Genomewide Analyses Define Different Modes of Transcriptional Regulation by Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) [J].
Adhikary, Till ;
Kaddatz, Kerstin ;
Finkernagel, Florian ;
Schoenbauer, Anne ;
Meissner, Wolfgang ;
Scharfe, Maren ;
Jarek, Michael ;
Bloecker, Helmut ;
Mueller-Bruesselbach, Sabine ;
Mueller, Rolf .
PLOS ONE, 2011, 6 (01)
[4]   CLONING OF A PROTEIN THAT MEDIATES TRANSCRIPTIONAL EFFECTS OF FATTY-ACIDS IN PREADIPOCYTES - HOMOLOGY TO PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS [J].
AMRI, EZ ;
BONINO, F ;
AILHAUD, G ;
ABUMRAD, NA ;
GRIMALDI, PA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (05) :2367-2371
[5]   Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer [J].
Barak, Y ;
Liao, D ;
He, WM ;
Ong, ES ;
Nelson, MC ;
Olefsky, JM ;
Boland, R ;
Evans, RM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (01) :303-308
[6]   PPARδ:: a dagger in the heart of the metabolic syndrome [J].
Barish, GD ;
Narkar, VA ;
Evans, RM .
JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (03) :590-597
[7]   The PPARβ/δ Activator GW501516 Prevents the Down-Regulation of AMPK Caused by a High-Fat Diet in Liver and Amplifies the PGC-1α-Lipin 1-PPARα Pathway Leading to Increased Fatty Acid Oxidation [J].
Barroso, Emma ;
Rodriguez-Calvo, Ricardo ;
Serrano-Marco, Lucia ;
Astudillo, Alma M. ;
Balsinde, Jesus ;
Palomer, Xavier ;
Vazquez-Carrera, Manuel .
ENDOCRINOLOGY, 2011, 152 (05) :1848-1859
[8]   PPARs: therapeutic targets for metabolic disease [J].
Berger, JP ;
Akiyama, TE ;
Meinke, PT .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2005, 26 (05) :244-251
[9]   Peroxisome proliferator-activated receptor-δ upregulates 14-3-3ε in human endothelial cells via CCAAT/enhancer binding protein-β [J].
Brunelli, Luca ;
Cieslik, Katarzyna A. ;
Alcorn, Joseph L. ;
Vatta, Matteo ;
Baldini, Antonio .
CIRCULATION RESEARCH, 2007, 100 (05) :E59-E71
[10]   RXRα and LXR activate two promoters in placenta- and tumor-specific expression of PLAC1 [J].
Chen, Y. ;
Moradin, A. ;
Schlessinger, D. ;
Nagaraja, R. .
PLACENTA, 2011, 32 (11) :877-884