Abstract P4-09-11: Fatty Acid Synthase (FASN) expression in Triple-Negative Breast Cancer

Abstract Background: In approximately 15–20% of patients with breast cancer, the tumors do not express estrogen receptor (ER), progesterone receptor (PR) and do not have amplification of HER2. These tumors are called triple-negative breast cancer (TNBC) and patients with these tumors have a poor prognosis. There is no clinically validated, molecularly targeted therapy for TNBC patients and they can be treated only with chemotherapy. Thus, the identification of a novel targeted therapies for TNBC patients would be of great benefit. Fatty acid synthase (FASN) is a multi-enzyme protein that catalyzes fatty acid synthesis. Its main reaction is to synthesize palmitate from acetyl-CoA and malonyl-CoA, in the presence of NADPH, into long-chain saturated fatty acids. Expression levels of FASN are low or undetectable in normal human tissues except for the liver and the adipose tissue. In contrast, high levels of FASN expression have been detected in several human carcinomas. Several reports highlight that FASN overexpression in tumor samples correlates with progression, aggressiveness and metastatic potential of the disease. Previously, our group has shown that FASN activity inhibition induces apoptosis in several human cancer cells. The aim of our study was to evaluate the expression of tumor levels of FASN in triple-negative breast cancer patients. Methods: FASN tumor expression was retrospectively evaluated in 30 paraffin-embedded core-biopsies of 30 patients with TNBC using the Fatty Acid Synthase polyclonal antibody (Assay design, Enzo Life Sciences, Exeter United Kingdom) and the detection kit EnVision™ (DAKO, Glostrup, Denmark). FASN expression levels were determined by immunohistochemistry (IHC) using the AutostainerPlus Link (DAKO). FASN expression was graded from 0 to 3+, meaning 0–1+ normal amounts of FASN protein compared to non-tumor breast tissue, 2+ moderate amounts and 3+ highest levels of FASN expression. In vitro, we have determined the effect of the FASN-inhibitors, EGCG and G28UCM, on cell viability (measured by the MTT assay) and apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase (PARP)] of two TNBC cell lines, MDA-MB-231 and MDA-MB-468. Results: From 30 patients with TNBC, 66.6% (20/30) of the patients had a high expression of FASN (FASN 3+) and 33.3% (10/30) had a moderate expression of FASN (FAS 2+). None of the tumors had lack of FASN expression analysed by immunohistochemistry. In vitro, the FASN-inhibitor G28UCM induced apoptosis and showed low IC50 values of citotoxicity in both, MDA-MB-231 and MDA-MB-468 TNBC cell lines. Conclusions: FASN is overexpressed in triple-negative breast cancer tumors. The absence of target therapies for this breast cancer subtype and its poor prognosis lead to the exploration of FASN as therapeutic target for TNBC patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-11.