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

Abstract

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.

Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors

“…More than being a marker of PrlR I146L constitutive activity, phosphorylated STAT5 is a thus good candidate contributing to the pathogenesis of MFAs. The molecular pathways that could mediate its effects may involve FAS, as the latter was proposed to stimulate survival and proliferation of breast cancer cells via complex mechanisms interfering with ER actions (31). Similar mechanisms could also occur in MFA, in which ER expression was also assessed (not shown).…”

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

“…FASN is a complex multifunctional enzyme that plays a central role in endogenous lipogenesis in mammals [28,29] . It has been reported that the overexpression of FASN together with a high proliferative index of breast cancer cells are associated with a nine-fold increased risk of patient mortality [30] . Accordingly, we examined the level of FASN by comparing breast cancer cell lines with different proliferative capability.…”

SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

“…Among the enzymes involved in lipid biosynthesis in tumor cells, the most studied is FAS, which is regulated by different growth factor signaling, including epidermal growth factor (EGF), as well as by steroid hormoneinduced transduction pathways, including estradiol (E2) and its cognate receptor (ER) [13,18]. Downstream of the growth factors and steroid receptors, the phosphatidylinositol-3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways have been suggested to mediate FAS expression through the sterol regulatory element-binding protein 1c (SREBP-1c) [13,18].…”

“…Downstream of the growth factors and steroid receptors, the phosphatidylinositol-3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways have been suggested to mediate FAS expression through the sterol regulatory element-binding protein 1c (SREBP-1c) [13,18]. However, the up-regulation of FAS by activated growth factor receptors requires a complex signaling network [19,20].…”