Research article
Dietary fat increases solid tumor growth and metastasis of 4T1 murine mammary carcinoma cells and mortality in obesity-resistant BALB/c mice
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* Corresponding author: Jung H Yoon Park jyoon@hallym.ac.kr
1 Department of Food Science and Nutrition, College of Natural Sciences, Hallym University, 39 Hallymdaehak-gil, Chuncheon, 200-702, Korea
2 Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, 39 Hallymdaehak-gil, Chuncheon, 200-702, Korea
3 Department of Biochemistry, College of Medicine, Hallym University, 39 Hallymdaehak-gil, Chuncheon, 200-702, Korea
4 Korea Food Research Institute, 516 Baekhyun-dong, Bundang-gu, Sungnam, 463-746, Korea
5 Department of Agricultural Biotechnology and Center for Agricultural Biomaterials, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-921, Korea
Breast Cancer Research 2011, 13:R78 doi:10.1186/bcr2927
Published: 11 August 2011Abstract
Introduction
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.