Influence of fatty acid diets on gene expression in rat mammary epithelial cells

Medvedovic M, Gear R, Freudenberg JM, Schneider J, Bornschein R, Yan M, Mistry MJ, Hendrix H, Karyala S, Halbleib D, Heffelfinger S, Clegg DJ, Anderson MW. Influence of fatty acid diets on gene expression in rat mammary epithelial cells. Physiol Genomics 38: 80-88, 2009. First published April 7, 2009; doi:10.1152/physiolgenomics.00007.2009.-Background: This study examines the impact of dietary fatty acids on regulation of gene expression in mammary epithelial cells before and during puberty. Methods: Diets primarily consisted of n-9 monounsaturated fatty acids (olive oil), n-6 polyunsaturated fatty acids (safflower), saturated acids (butter), and the reference AIN-93G diet (soy oil). The dietary regimen mimics the repetitive nature of fatty acid exposure in Western diets. Diet-induced changes in gene expression were examined in laser capture microdissected mammary ductal epithelial cells at day of weaning and end of puberty. PCNA immunohistochemistry analysis compared proliferation rates between diets. Results: Genes differentially expressed between each test diets and the reference diet were significantly enriched by cell cycle genes. Some of these genes were involved in activation of the cell cycle pathway or the G2/M check point pathway. Although there were some differences in the level of differential expression, all diets showed qualitatively the same pattern of differential expression compared to the reference diet. Cluster analysis identified an expanded set of cell cycle as well as immunity and sterol metabolism related clusters of differentially expressed genes. Conclusion: Fatty acid-enriched diets significantly upregulated proliferation above normal physiological levels during puberty. Higher cellular proliferation during puberty caused by enriched fatty acid diets poses a potential increase risk of mammary cancer in later life. The human homologs of 27 of 62 cell cycle rat genes are included in a human breast cancer cluster of 45 cell cycle genes, further emphasizing the importance of our findings in the rat model.