Microarray gene expression analysis of fatty acid synthase (FAS) signaling on breast cancer cell lines

9690 Background: Fatty acid synthase (FAS) is the enzyme responsible for the de novo synthesis of fatty acids, and is overexpressed in 20% of human breast carcinomas. The inhibition of FAS induces apoptosis, and has shown significant antitumor activity against human breast, prostate and ovarian cancer xenografts. We have previously observed that inhibition of FAS acts synergistically with trastuzumab inhibiting the proliferation of HER2-positive, FAS positive breast cancer cells. We have also shown that inhibition of FAS enhances the effectiveness of paclitaxel, docetaxel and vinorelbine, and reverses anthracyclin resistance on breast cancer cells. We have now tested the effects of cerulenin, an inhibitor of FAS, on gene expression analysis of the breast cancer cell lines SK-Br-3, BT-474, and MCF-7, which express different levels of FAS (++, +, and negative). Methods: Using 10,000-spot human cDNA microarrays, we have evaluated the time course of the transcriptional response of breast cancer cells to FAS inhibition (6 to 24h). Results: Gene response paralelled the magnitude and time-course of FAS enzymatic inhibition. In FAS-positive cells, significant up-regulation (>6-fold) was observed for osteonectin, TGF-β2, and genes involved in the insulin signalling pathway (IGFBP-1, IGFBP-2, IGFBP-3 and IGF5), apoptosis (caspase-7, Gas-7, Gas-1), and metastasis inhibition (thrombospondin, osteoprotegirin, kiss-1). Significant down-regulation (>6-fold) was observed for Grb7 (involved in HER2-signalling pathway), FGF5, inhibin, and IL-11. Conclusions: The observed changes on the gene expression pattern provide new insights in the molecular mechanisms of the inhibition of FAS, and will help in the development of new inhibitory molecules. No significant financial relationships to disclose.