The formation of TOS tubules and the migration of these entities drive the organization of the local cell population to generate a new architectural entity, the solid tumor. This is the first biomechanical/structural model of solid tumor formation, invasion and metastasis that integrates current biophysical theories of solid tumor formation with the formation of specific biological cell structures responsible for many of the genetic, physiological and biochemical parameters that characterize malignant transformation. O61 EGFR Signaling Mediates Metabolism-Dependent Epigenetic Control in a Model of Human Breast Cancer. CPT1A is a Novel Partner of Histone Deacetylase
1 in Cell Death Escaping Mechanisms Paola Mazzarelli 1 , Sabina Pucci1, Maria J. Zonetti1, Luigi G. Spagnoli1 1 Department of
Biopathology, University of Rome Tor Vergata, Rome, Italy The altered metabolism Acadesine manufacturer of tumor cells may be a potential means by which these cells evade programmed cell death, favouring survival and tumoral growth. In particular, lipid Apoptosis inhibitor metabolism is markedly altered in the tumoral context. Neoplastic cells use endogenously synthesized fatty acids to satisfy their metabolic necessities and fatty acids synthase (FASN), the major enzyme required for the synthesis of fatty acids, is up-regulated in a wide array of solid tumors. Experiments of RNA interference-knockdown have confirmed its role as metabolic oncogene. ErbB2 receptor, amplified in 25% of breast cancers, has been recognized as activator of FASN promoter. Thus, Epidermal growth factor receptor (EGFR) family system, activated in tumor microenviroment, could influence FASN activity via Her2 activation. We previously studied human breast carcinomas
and breast cancer cell lines (SK-BR3, BT474, MCF-7) with or without Her2 gene amplification confirming that FASN was over-expressed in a high GSK1210151A clinical trial percent of cases and that FASN expression levels could be Phenylethanolamine N-methyltransferase indicators of Her2 transduction activity (unpublished data). On the other hand, we found an inhibition of fatty-acids b-oxidation in the tumoral context. In particular carnitine palmitoyl transferase I (CPT I), the rate-limiting enzyme in the transport of long-chain fatty acids for b-oxidation, was significantly decreased in the mitochondria and it strikingly localized in the nuclei of tumoral samples, where it could be implicated in the epigenetic regulation of transcription by its link to HDAC1. Here we report that the silencing of CPT1A nuclear expression by small interfering RNAs is a sufficient condition to induce apoptosis in MCF-7 breast cancer cells. The apoptosis triggered by RNA interference correlates with reduction of HDAC activity and hyperacetylation of histone- and non histone-proteins, involved in cancer-relevant death pathways.