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Biological features of core networks that result from a high-fat diet in hepatic and pulmonary tissues in mammary tumour-bearing, obesity-resistant mice

  • Eun Ji Kim (a1), Hea Young Oh (a2), Hyoung-Sam Heo (a2), Ji Eun Hong (a1), Sung-Jae Jung (a2) (a3), Ki Won Lee (a4), Jong Hoon Park (a5), Cheol-Goo Hur (a2) and Jung Han Yoon Park (a1) (a6)...


We previously demonstrated that the chronic consumption of a high-fat diet (HFD) promotes lung and liver metastases of 4T1 mammary carcinoma cells in obesity-resistant BALB/c mice. To examine early transcriptional responses to tumour progression in the liver and lungs of HFD-fed mice, 4-week-old female BALB/c mice were divided into four groups: sham-injected, control diet (CD)-fed; sham-injected, HFD-fed (SH); 4T1 cell-injected, CD-fed (TC); 4T1 cell-injected, HFD-fed (TH). Following 16 weeks of either a CD or HFD, 4T1 cells were injected into the mammary fat pads of mice in the TC and TH groups and all mice were continuously fed identical diets. At 14 d post-injection, RNA was isolated from hepatic and pulmonary tissues for microarray analysis of mRNA expression. Functional annotation and core network analyses were conducted for the TH/SH Unique gene set. Inflammation in hepatic tissues and cell mitosis in pulmonary tissues were the most significant biological functions in the TH/SH Unique gene set. The biological core networks of the hepatic TH/SH Unique gene set were characterised as those genes involved in the activation of acute inflammatory responses (Orm1, Lbp, Hp and Cfb), disordered lipid metabolism and deregulated cell cycle progression. Networks of the pulmonary Unique gene set displayed the deregulation of cell cycle progression (Cdc20, Cdk1 and Bub1b). These HFD-influenced alterations may have led to favourable conditions for the formation of both pro-inflammatory and pro-mitotic microenvironments in the target organs that promote immune cell infiltration and differentiation, as well as the infiltration and proliferation of metastatic tumour cells.

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Corresponding author

*Corresponding authors: C.-G. Hur, fax +82 42 879 8569, email; J. H. Y. Park, fax +82 33 256 0199, email


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1Desantis, C, Siegel, R, Bandi, P, et al. (2011) Breast cancer statistics, 2011. CA Cancer J Clin 61, 409418.
2Steeg, PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12, 895904.
3Hauner, H & Hauner, D (2010) The impact of nutrition on the development and prognosis of breast cancer. Breast Care 5, 377381.
4Thiebaut, AC, Kipnis, V, Chang, SC, et al. (2007) Dietary fat and postmenopausal invasive breast cancer in the National Institutes of Health-AARP Diet and Health Study cohort. J Natl Cancer Inst 99, 451462.
5Patterson, RE, Cadmus, LA, Emond, JA, et al. (2010) Physical activity, diet, adiposity and female breast cancer prognosis: a review of the epidemiologic literature. Maturitas 66, 515.
6Heitmann, BL, Lissner, L, Sorensen, TI, et al. (1995) Dietary fat intake and weight gain in women genetically predisposed for obesity. Am J Clin Nutr 61, 12131217.
7Kim, EJ, Choi, MR, Park, H, et al. (2011) Dietary fat increases solid tumor growth and metastasis of 4T1 murine mammary carcinoma cells and mortality in obesity-resistant BALB/c mice. Breast Cancer Res 13, R78.
8Paget, S (1889) The distribution of secondary growths in cancer of the breast. Lancet i, 571573.
9Hanahan, D & Weinberg, RA (2011) Hallmarks of cancer: the next generation. Cell 144, 646674.
10Hanahan, D & Coussens, LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309322.
11Jodele, S, Blavier, L, Yoon, JM, et al. (2006) Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression. Cancer Metastasis Rev 25, 3543.
12Weis, SM & Cheresh, DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17, 13591370.
13Weisberg, SP, McCann, D, Desai, M, et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112, 17961808.
14Xu, H, Barnes, GT, Yang, Q, et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112, 18211830.
15Park, H, Kim, M, Kwon, GT, et al. (2012) A high-fat diet increases angiogenesis, solid tumor growth, and lung metastasis of CT26 colon cancer cells in obesity-resistant BALB/c mice. Mol Carcinog 51, 869880.
16Huang da, W, Sherman, BT & Lempicki, RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4, 4457.
17Kim, EJ, Kang, IJ, Cho, HJ, et al. (2003) Conjugated linoleic acid downregulates insulin-like growth factor-I receptor levels in HT-29 human colon cancer cells. J Nutr 133, 26752681.
18Cho, HJ, Seon, MR, Lee, YM, et al. (2008) 3,3′-Diindolylmethane suppresses the inflammatory response to lipopolysaccharide in murine macrophages. J Nutr 138, 1723.
19Coffman, FD (2008) Chitinase 3-Like-1 (CHI3L1): a putative disease marker at the interface of proteomics and glycomics. Crit Rev Clin Lab Sci 45, 531562.
20Libreros, S, Garcia-Areas, R, Shibata, Y, et al. (2012) Induction of proinflammatory mediators by CHI3L1 is reduced by chitin treatment: decreased tumor metastasis in a breast cancer model. Int J Cancer 131, 377386.
21O'Reilly, MS, Boehm, T, Shing, Y, et al. (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277285.
22Cimino, D, Fuso, L, Sfiligoi, C, et al. (2008) Identification of new genes associated with breast cancer progression by gene expression analysis of predefined sets of neoplastic tissues. Int J Cancer 123, 13271338.
23Fornace, AJ Jr, Alamo, I Jr & Hollander, MC (1988) DNA damage-inducible transcripts in mammalian cells. Proc Natl Acad Sci U S A 85, 88008804.
24Marceau, N, Loranger, A, Gilbert, S, et al. (2001) Keratin-mediated resistance to stress and apoptosis in simple epithelial cells in relation to health and disease. Biochem Cell Biol 79, 543555.
25Tao, GZ, Looi, KS, Toivola, DM, et al. (2009) Keratins modulate the shape and function of hepatocyte mitochondria: a mechanism for protection from apoptosis. J Cell Sci 122, 38513855.
26Fillgrove, KL & Anderson, VE (2001) The mechanism of dienoyl-CoA reduction by 2,4-dienoyl-CoA reductase is stepwise: observation of a dienolate intermediate. Biochemistry 40, 1241212421.
27Landis, MD, Seachrist, DD, Abdul-Karim, FW, et al. (2006) Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors. Oncogene 25, 33253334.
28Landis, MD, Seachrist, DD, Montanez-Wiscovich, ME, et al. (2005) Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-beta signaling in ErbB2/Neu-induced tumors from transgenic mice. Oncogene 24, 51735190.
29Ursini-Siegel, J, Rajput, AB, Lu, H, et al. (2007) Elevated expression of DecR1 impairs ErbB2/Neu-induced mammary tumor development. Mol Cell Biol 27, 63616371.
30Shaffer, AL, Yu, X, He, Y, et al. (2000) BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199212.
31Park, EJ, Lee, JH, Yu, GY, et al. (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197208.
32Naugler, WE, Sakurai, T, Kim, S, et al. (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121124.
33He, G, Yu, GY, Temkin, V, et al. (2010) Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17, 286297.
34Rubinstein, N, Alvarez, M, Zwirner, NW, et al. (2004) Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; a potential mechanism of tumor-immune privilege. Cancer Cell 5, 241251.
35Stetler-Stevenson, WG (2008) Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal 1, re6.
36Nakayama, KI & Nakayama, K (2006) Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6, 369381.
37Uesugi, T, Froh, M, Arteel, GE, et al. (2002) Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice. J Immunol 168, 29632969.
38Su, GL, Gong, KQ, Fan, MH, et al. (2005) Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice. Hepatology 41, 187195.
39Li, Q, Li, YX, Stahl, GL, et al. (2011) Essential role of factor B of the alternative complement pathway in complement activation and opsonophagocytosis during acute pneumococcal otitis media in mice. Infect Immun 79, 25782585.
40Taube, C, Thurman, JM, Takeda, K, et al. (2006) Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation. Proc Natl Acad Sci U S A 103, 80848089.
41Irmak, S, Oliveira-Ferrer, L, Singer, BB, et al. (2009) Pro-angiogenic properties of orosomucoid (ORM). Exp Cell Res 315, 32013209.
42Thompson, DK, Haddow, JE, Smith, DE, et al. (1983) Elevated serum acute phase protein levels as predictors of disseminated breast cancer. Cancer 51, 21002104.
43Abd Hamid, UM, Royle, L, Saldova, R, et al. (2008) A strategy to reveal potential glycan markers from serum glycoproteins associated with breast cancer progression. Glycobiology 18, 11051118.
44Thompson, S, Cantwell, BM, Cornell, C, et al. (1991) Abnormally-fucosylated haptoglobin: a cancer marker for tumour burden but not gross liver metastasis. Br J Cancer 64, 386390.
45Hanamura, N, Yoshida, T, Matsumoto, E, et al. (1997) Expression of fibronectin and tenascin-C mRNA by myofibroblasts, vascular cells and epithelial cells in human colon adenomas and carcinomas. Int J Cancer 73, 1015.
46Inufusa, H, Nakamura, M, Adachi, T, et al. (1995) Localization of oncofetal and normal fibronectin in colorectal cancer. Correlation with histologic grade, liver metastasis, and prognosis. Cancer 75, 28022808.
47van der Meer, DL, Degenhardt, T, Vaisanen, S, et al. (2010) Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis. Nucleic Acids Res 38, 28392850.
48Astruc, M, Tabacik, C, Descomps, B, et al. (1977) Squalene epoxidase and oxidosqualene lanosterol-cyclase activities in cholesterogenic and non-cholesterogenic tissues. Biochim Biophys Acta 487, 204211.
49Helms, MW, Kemming, D, Pospisil, H, et al. (2008) Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease. Br J Cancer 99, 774780.
50Mandard, S, Muller, M & Kersten, S (2004) Peroxisome proliferator-activated receptor alpha target genes. Cell Mol Life Sci 61, 393416.
51Young, CD & Anderson, SM (2008) Sugar and fat – that's where it's at: metabolic changes in tumors. Breast Cancer Res 10, 202.
52Lindquist, S (1986) The heat-shock response. Annu Rev Biochem 55, 11511191.
53Davidoff, AM, Iglehart, JD & Marks, JR (1992) Immune response to p53 is dependent upon p53/HSP70 complexes in breast cancers. Proc Natl Acad Sci U S A 89, 34393442.
54Sherman, MY, Gabai, V, O'Callaghan, C, et al. (2007) Molecular chaperones regulate p53 and suppress senescence programs. FEBS Lett 581, 37113715.
55Srethapakdi, M, Liu, F, Tavorath, R, et al. (2000) Inhibition of Hsp90 function by ansamycins causes retinoblastoma gene product-dependent G1 arrest. Cancer Res 60, 39403946.
56Becker, B, Multhoff, G, Farkas, B, et al. (2004) Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp Dermatol 13, 2732.
57Sidera, K, Samiotaki, M, Yfanti, E, et al. (2004) Involvement of cell surface HSP90 in cell migration reveals a novel role in the developing nervous system. J Biol Chem 279, 4537945388.
58Yamamoto, M, Sato, S, Hemmi, H, et al. (2002) Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324329.
59Akira, S (2006) TLR signaling. Curr Top Microbiol Immunol 311, 116.
60Bihl, F, Germain, C, Luci, C, et al. (2011) Mechanisms of NK cell activation: CD4(+) T cells enter the scene. Cell Mol Life Sci 68, 34573467.
61Airoldi, I & Ribatti, D (2011) Regulation of angiostatic chemokines driven by IL-12 and IL-27 in human tumors. J Leukoc Biol 90, 875882.
62Rakhmilevich, AL, Janssen, K, Hao, Z, et al. (2000) Interleukin-12 gene therapy of a weakly immunogenic mouse mammary carcinoma results in reduction of spontaneous lung metastases via a T-cell-independent mechanism. Cancer Gene Ther 7, 826838.
63Shi, X, Cao, S, Mitsuhashi, M, et al. (2004) Genome-wide analysis of molecular changes in IL-12-induced control of mammary carcinoma via IFN-gamma-independent mechanisms. J Immunol 172, 41114122.
64Liu, FT & Rabinovich, GA (2005) Galectins as modulators of tumour progression. Nat Rev Cancer 5, 2941.
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