Fatty Acid Synthase is a Novel Regulator of Her-2/neu (erbB-2) Oncogene in Breast Cancer Cells

摘要

Fatty Acid Synthase (FAS)-catalyzed de novo fatty-acid biosynthesis, an anabolic-energy-storage pathway largely considered of minor importance in humans, has been linked to tumor virulence and poor prognosis in population studies of several human malignancies. As a part of our efforts to assess the role of FAS on the survival and proliferation of cancer cells, we recently identified a novel bi-directional molecular linkage between tumor-associated FAS and Her-2/neu (erbB-2) oncogene, a well-characterized poor prognosis marker that is overexpressed in about 30% of breast carcinomas. First, when FAS protein expression was characterized in a wide panel of human breast cancer cell lines, a positive correlation was found between high levels of FAS expression and the amplification and/or overexpression of Her-2lneu oncogene. Second, Her-2/neu overexpression stimulated the activity of FAS gene promoter and ultimately mediated increased endogenous fatty acid biosynthesis, and this Her-2/neu-induced up-regulation of breast cancer-associated FAS was inhibitable by anti-Her-2/neu antibodies such as trastuzumab. Third, pharmacological inhibition of breast cancer-associated FAS hyperactivity negatively regulated the expression of Her-2/neu-coded pl85~(Her-2/neu)oncoprotein. Similarly, RNA interference (RNAi)-mediated silencing of FAS gene expression promoted a dramatic inhibition of Her-2/ neu. Pharmacological and RNAi-induced inhibition of FAS specifically repressed Her-2/neu gene expression by up-regulating the expression of the Ets class transcription factor PEA3, which attenuates Her-2/neu promoter activity. This, in turn, synergistically sensitized breast cancer cells exhibiting amplification and/or overexpression of Ker-2/neu oncogene to trastuzumab-induced cell growth inhibition and apoptotic cell death. Fourth, FAS played a necessary role in the oncogenic activity of Her-2/neu as its inhibition suppressed the state of malignant transformation of Her-2/neu-overexpressing NIH-3T3 fibroblasts. Fifth, the degree of Her-2/neu oncogene expression, and not FAS overexpression, predicted breast cancer cell sensitivity to chemical FAS blockers. These findings provide compelling evidence that FAS-driven cellular signaling actively participates in the maintenance and/or enhancement of Her-2/neu-regulated breast carcinomas. Importantly, Her-2/neu oncogene appears to act as an energy sensor in the response of breast cancer cells to a nongenotoxic metabolic stress, such as the perturbation of FAS-dependent endogenous fatty acid biosynthesis, thus supporting the notion that FAS inhibition is a novel molecular strategy to selectively kill breast cancer cells harboring high levels of Her-2/neu oncogene.