Characterization of Fatty Acid Synthase (FAS) as a Predictive Marker of Breast Cancer Sensitivity to Chemotherapy.

摘要

The expression and activity of Fatty Acid Synthase (FASN), the sole protein in the human genome capable of de novo FA biogenesis, is extremely low in nearly all non-malignant adult tissues, whereas significant overexpression and concurrent increased activity of FASN represents an early and nearly universal phenotypic alteration in most human cancers. This creates a large therapeutic index and, therefore, FASN-driven endogenous FA synthesis pathway may provide a number of avenues of future exploration applicable to the prevention and/or treatment of cancer disease. Upon FASN blockade, cancer cells stop proliferating and ultimately die mainly through the process of apoptosis. Since solid tumors display a complex drug resistant phenotype that involves inherent an acquired mechanisms, and because up-regulation of FASN associates with poorer prognosis in important subsets of human carcinomas, we formerly theorized that tumor-associated FASN plays a causal role in the response to anti-cancer treatments. In the last few years our group has evaluated whether chemical FASN blockers as well as RNA silencing interference techniques directed against FASN gene may provide a mean to increase efficacy over existing therapy in human breast carcinomas. Her, we perimentally review how the FASN-related 11lipogenic phenotype" actively regulates the efficacy of anthracyclines (i.e., doxorubicin), microtubule-interfering agents (i.e., paclitaxel, docetaxel, and vinorelbine), nucleotide analogues (i.e., 5-Fluorouracil), and monoclonal antibodies (i.e., trastuzumab) in cultured breast cancer cells. Inherent and acquired drug resistance hampers successful treatment in many human malignancies, and its prevention or reversal is still awaiting new therapeutic strategies or pharmaceuticals.