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Targeting Fatty Acid Synthase in Breast and Endometrial Cancer: An Alternative to Selective Estrogen Receptor Modulators?

Department of Medicine (R.L.), Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201; Department of Medicine (R.L.), Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60211; Robert H. Lurie Comprehensive Cancer Center of Northwestern University (R.L.), Chicago, Illinois 60611; Fundació d’ Investigació Biomèdica de Girona Dr. Josep Trueta (J.A.M.), 17007 Girona, Catalonia, Spain; Institut Catalá d’ Oncología de Girona-Hospital Universitari de Girona Dr. Josep Trueta, Girona (J.A.M.), 170010 Catalonia, Spain

Address all correspondence and requests for reprints to: Ruth Lupu, Ph.D., Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, Illinois 60201. E-mail: r-lupu{at}northwestern.edu.

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.

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