Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators?
There is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the estradiol (E2)/estrogen receptor (ER) signaling in breast cancer. In this regard, new information on the mechanisms of E2/ER function and/or cross talk with other prosurvival cascades should provide the basis for the development of other ideal anti-E2 therapies with the intent to enhance clinical efficacy, reduce side effects or both. Our very recent assessment of the mechanisms by which cancer-associated increased lipogenesis and its inhibition alters the E2/ER signaling discovered that fatty acid synthase (FASN), the enzyme catalyzing the terminal steps in the de novo biosynthesis of long-chain fatty acids, differentially modulates the state of sensitivity of breast and endometrial cancer cells to E2-stimulated ER transcriptional activation and E2-dependent cell growth and survival: 1) pharmacological inhibition of FASN activity induced a dramatic augmentation of E2-stimulated ER-driven gene transcription, whereas interference (RNAi)-mediated silencing of FAS gene expression drastically lowered E2 requirements for optimal activation of ER transcriptional activation in breast cancer cells; conversely, pharmacological and RNAi-induced inhibition of FASN worked as an antagonist of E2- and tamoxifen-dependent ER transcriptional activity in endometrial adenocarcinoma cells; 2) pharmacological and RNAi-induced inhibition of FASN synergistically enhanced E2-mediated down-regulation of ER protein and mRNA expression in breast cancer cells, whereas specific FASN blockade resulted in a marked down-regulation of E2-stimulated ER expression in endometrial cancer cells; and 3) FASN inhibition decreased cell proliferation and cell viability by promoting apoptosis in hormone-dependent breast and endometrial cancer cells. In this review we propose that, through a complex mechanism involving the regulation of MAPK/ER cross talk as well as critical E2-related proteins including the Her-2/neu (erbB-2) oncogene and the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(Kip1), a previously unrevealed connection exists between FASN and the genomic and nongenomic ER activities in breast and endometrial cancer cells. From a clinical perspective, we suggest that if chemically stable FASN inhibitors or cell-selective systems able to deliver RNAi targeting FASN gene demonstrate systemic anticancer effects of FASN inhibition in vivo, additional preclinical studies to characterize their anti-breast cancer actions should be of great interest as the specific blockade of FASN activity may also provide a protective means against endometrial carcinoma associated with tamoxifen-based breast cancer therapy.
Lupu
Ruth
R
Department of Medicine, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, Illinois 60201, USA. r-lupu@northwestern.edu
Menendez
Javier A
JA
D001943:Breast Neoplasms / Q000188:drug therapy*; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004958:Estradiol / Q000502:physiology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D034741:RNA, Small Interfering / Q000494:pharmacology; D011959:Receptors, Estradiol / Q000502:physiology; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D034741:RNA, Small Interfering; D011959:Receptors, Estradiol; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol; D064429:Fatty Acid Synthases