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http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum
Minireview: Targeting Fatty Acid Synthase (FASN) in Breast and Endometrial Cancer: An alternative to Selective Estrogen Receptor Modulators (SERMs)?
* Lupu R,
* Menendez JA.
Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL, USA; Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA; Fundacio d' Investigacio Biomedica de Girona Dr. Josep Trueta (IdIBGi), Girona, Catalonia, Spain; Institut Catala d' Oncologia de Girona (ICO Girona)- Hospital Universitari de Girona Dr. Josep Trueta, Girona, Catalonia, Spain.
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 pro-survival cascades should provide the basis for the development of other "ideal" anti-E2 therapies with the intent to enhance clinical efficacy and 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, while 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 (TAM)-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, while 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 crosstalk as well as critical E2-related proteins including the Her-2/neu (erbB-2) oncogene and the Cyclin-Dependent Kinase Inhibitors (CDKis) p21(WAF1/CIP1) and p27(Kip1), a previously unrevealed connection exists between FASN and the genomic and non-genomic 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 TAM-based breast cancer therapy.
PMID: 16809439 [PubMed - as supplied by publisher]
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