Genome-wide changes accompanying knockdown of fatty acid synthase in breast cancer.
BACKGROUND
The lipogenic enzyme fatty acid synthase (FAS) is up-regulated in a wide variety of cancers, and is considered a potential metabolic oncogene by virtue of its ability to enhance tumor cell survival. Inhibition of tumor FAS causes both cell cycle arrest and apoptosis, indicating FAS is a promising target for cancer treatment.


RESULTS
Here, we used gene expression profiling to conduct a global study of the cellular processes affected by siRNA mediated knockdown of FAS in MDA-MB-435 mammary carcinoma cells. The study identified 169 up-regulated genes (> or = 1.5 fold) and 110 down-regulated genes (< or = 0.67 fold) in response to knockdown of FAS. These genes regulate several aspects of tumor function, including metabolism, cell survival/proliferation, DNA replication/transcription, and protein degradation. Quantitative pathway analysis using Gene Set Enrichment Analysis software further revealed that the most pronounced effect of FAS knockdown was down-regulation in pathways that regulate lipid metabolism, glycolysis, the TCA cycle and oxidative phosphorylation. These changes were coupled with up-regulation in genes involved in cell cycle arrest and death receptor mediated apoptotic pathways.


CONCLUSIONS
Together these findings reveal a wide network of pathways that are influenced in response to FAS knockdown and provide new insight into the role of this enzyme in tumor cell survival and proliferation.
Knowles
Lynn M
LM
Cancer Research Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA. lknowles@burnham.org <lknowles@burnham.org>
Smith
Jeffrey W
JW
D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D064429:Fatty Acid Synthases / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015894:Genome, Human; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D015854:Up-Regulation
D034741:RNA, Small Interfering; D064429:Fatty Acid Synthases