This Article Full Text Full Text (PDF) All Versions of this Article: 147/9/4056    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lupu, R. Articles by Menendez, J. A. Search for Related Content PubMed PubMed Citation Articles by Lupu, R. Articles by Menendez, J. A.

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.

This article has been cited by other articles:

				J. H. Suh, E.-Y. Gong, J. B. Kim, I.-K. Lee, H.-S. Choi, and K. Lee Sterol Regulatory Element-Binding Protein-1c Represses the Transactivation of Androgen Receptor and Androgen-Dependent Growth of Prostatic Cells Mol. Cancer Res., February 1, 2008; 6(2): 314 - 324. [Abstract] [Full Text] [PDF]