Genome-wide changes accompanying knockdown of fatty acid synthase in breast cancer

BMC Genomics. 2007 Jun 12;8:168. doi: 10.1186/1471-2164-8-168.

Abstract

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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis / genetics
  • Breast Neoplasms / genetics*
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Down-Regulation
  • Fatty Acid Synthases / genetics*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genome, Human*
  • Humans
  • Metabolic Networks and Pathways / genetics*
  • RNA, Small Interfering / pharmacology*
  • Up-Regulation

Substances

  • RNA, Small Interfering
  • Fatty Acid Synthases