title: Dietary fat increases solid tumor growth and metastasis of 4T1 murine mammary carcinoma cells and mortality in obesity-resistant BALB/c mice.
abstract: BACKGROUND
  High-fat diets (HFDs) are known to cause obesity and are associated with breast cancer progression and metastasis. Because obesity is associated with breast cancer progression, it is important to determine whether dietary fat per se stimulates breast cancer progression in the absence of obesity. This study investigated whether an HFD increases breast cancer growth and metastasis, as well as mortality, in obesity-resistant BALB/c mice.
  
  
  METHODS
  The 4-week-old, female BALB/c mice were fed HFD (60% kcal fat) or control diet (CD, 10% kcal fat) for 16 weeks. Subsequently, 4T1 mammary carcinoma cells were injected into the inguinal mammary fat pads of mice fed continuously on their respective diets. Cell-cycle progression, angiogenesis, and immune cells in tumor tissues, proteases and adhesion molecules in the lungs, and serum cytokine levels were analyzed with immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assay (ELISA). In vitro studies were also conducted to evaluate the effects of cytokines on 4T1 cell viability, migration, and adhesion.
  
  
  RESULTS
  Spleen and gonadal fat-pad weights, tumor weight, the number and volume of tumor nodules in the lung and liver, and tumor-associated mortality were increased in the HFD group, with only slight increases in energy intake and body weight. HF feeding increased macrophage infiltration into adipose tissues, the number of lipid vacuoles and the expression of cyclin-dependent kinase (CDK)2, cyclin D1, cyclin A, Ki67, CD31, CD45, and CD68 in the tumor tissues, and elevated serum levels of complement fragment 5a (C5a), interleukin (IL)-16, macrophage colony-stimulating factor (M-CSF), soluble intercellular adhesion molecule (sICAM)-1, tissue inhibitors of metalloproteinase (TIMP)-1, leptin, and triggering receptor expressed on myeloid cells (TREM)-1. Protein levels of the urokinase-type plasminogen activator, ICAM-1, and vascular cell adhesion molecule-1 were increased, but plasminogen activator inhibitor-1 levels were decreased in the lungs of the HFD group. In vitro assays using 4T1 cells showed that sICAM-1 increased viability; TREM-1, TIMP-1, M-CSF, and sICAM-1 increased migration; and C5a, sICAM-1, IL-16, M-CSF, TIMP-1, and TREM-1 increased adhesion.
  
  
  CONCLUSIONS
  Dietary fat increases mammary tumor growth and metastasis, thereby increasing mortality in obesity-resistant mice.
authors.affiliation: Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, 39 Hallymdaehak-gil, Chuncheon, 200-702, Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Kim
authors.forename: Mi-Ran
authors.initials: MR
authors.lastname: Choi
authors.forename: Heesook
authors.initials: H
authors.lastname: Park
authors.forename: Minhee
authors.initials: M
authors.lastname: Kim
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Hong
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Hyang Sook
authors.initials: HS
authors.lastname: Chun
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Jung Han
authors.initials: JH
authors.lastname: Yoon Park
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015936:Complement C5a / Q000378:metabolism; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D002149:Energy Intake / Q000187:drug effects; D005260:Female; D019410:Interleukin-16 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000401:mortality* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000473:pathology; D009765:Obesity / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015936:Complement C5a; D019925:Cyclin A; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D016207:Cytokines; D004041:Dietary Fats; D019410:Interleukin-16; D019394:Ki-67 Antigen; D020738:Leptin; D017493:Leukocyte Common Antigens; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C530105:Ccnd1 protein, mouse; C495893:Cdk2 protein, mouse; C516770:Ptprc protein, mouse