Antiestrogens are effective therapies for the management of many estrogen receptor-α (ER)-positive breast cancers. Nonetheless, both de novo and acquired resistance occur and remain major problems in the clinical setting. IFNγ is an inflammatory cytokine that induces the expression and function of IFN regulatory factor 1 (IRF1), a tumor suppressor gene that can increase antiestrogen responsiveness. We show that IFNγ, but not IFNα, IFNβ, or fulvestrant (ICI; ICI 182,780; Faslodex), induces IRF1 expression in antiestrogen-resistant MCF7/LCC9 and LY2 cells. Moreover, IFNγ restores the responsiveness of these cells to fulvestrant. Increased IRF1 activation suppresses NF-κB p65 (RELA) activity, inhibits the expression of prosurvival (BCL2, BCL-W), and induces the expression of proapoptotic members (BAK, mitochondrial BAX) of the BCL2 family. This molecular signaling is associated with the activation of signal transducer and activator of transcription 1 and leads to increased mitochondrial membrane permeability; activation of caspase-7 (CASP7), CASP8, and CASP9; and induction of apoptosis but not autophagy. Whereas antiestrogen-resistant cells are capable of inducing autophagy through IFN-mediated signaling, their ability to do so through antiestrogen-regulated signaling is lost. The abilities of IFNγ to activate CASP8, induce apoptosis, and restore antiestrogen sensitivity are prevented by siRNA targeting IRF1, whereas transient overexpression of IRF1 mimics the effects of IFNγ treatment. These observations support the exploration of clinical trials combining antiestrogens and compounds that can induce IRF1, such as IFNγ, for the treatment of some ER-positive breast cancers. Mol Cancer Ther; 9(5); 1274-85. ©2010 AACR.

Hyperlipidemia is one of the most important risk factors for atherosclerosis. This can be amplified by a localized inflammatory response mediated by macrophages. Macrophages are capable of taking up excess cholesterol, and it is well known that delivery of cholesterol to the mitochondria by steroidogenic acute regulatory (StAR) protein is the rate-limiting step for cholesterol degradation in the liver. It has also been shown that overexpression of StAR in hepatocytes dramatically increases the amount of regulatory oxysterols in the nucleus, which play an important role in the maintenance of intracellular lipid homeostasis. The goal of the present studywas to determine whether StAR plays a similar role in macrophages. We have found that overexpression of StAR in human THP-1 monocyte-derived macrophages decreases intracellular lipid levels, activates liver X receptor alpha (LXRα) and proliferation peroxysome activator receptor gamma (PPARγ), and increases ABCG1 and CYP27A1 expression. Furthermore, it reduces the secretion of inflammatory factors, and prevents apoptosis. These results suggest that StAR delivers cholesterol to mitochondria where regulatory oxysterols are generated. Regulatory oxysterols can in turn activate nuclear receptors, which increase expression of cholesterol efflux transporters, and decrease secretion of inflammatory factors. These effects can prevent macrophage apoptosis. These results imply a potential role of StAR in the prevention of atherosclerosis.

Ren S, Ning Y. Sulfation of 25-hydroxycholesterol regulates lipid metabolism, inflammatory responses, and cell proliferation. Am J Physiol Endocrinol Metab 306: E123-E130, 2014. First published December 3, 2013 doi:10.1152/ajpendo.00552.2013.-Intracellular lipid accumulation, inflammatory responses, and subsequent apoptosis are the major pathogenic events of metabolic disorders, including atherosclerosis and nonalcoholic fatty liver diseases. Recently, a novel regulatory oxysterol, 5-cholesten-3b, 25-diol 3-sulfate (25HC3S), has been identified, and hydroxysterol sulfotransferase 2B1b (SULT2B1b) has been elucidated as the key enzyme for its biosynthesis from 25-hydroxycholesterol (25HC) via oxysterol sulfation. The product 25HC3S and the substrate 25HC have been shown to coordinately regulate lipid metabolism, inflammatory responses, and cell proliferation in vitro and in vivo. 25HC3S decreases levels of the nuclear liver oxysterol receptor (LXR) and sterol regulatory element-binding proteins (SREBPs), inhibits SREBP processing, subsequently downregulates key enzymes in lipid biosynthesis, decreases intracellular lipid levels in hepatocytes and THP-1-derived macrophages, prevents apoptosis, and promotes cell proliferation in liver tissues. Furthermore, 25HC3S increases nuclear PPAR␥ and cytosolic IB␣ and decreases nuclear NF-B levels and proinflammatory cytokine expression and secretion when cells are challenged with LPS and TNF␣. In contrast to 25HC3S, 25HC, a known LXR ligand, increases nuclear LXR and decreases nuclear PPARs and cytosol IB␣ levels. In this review, we summarize our recent findings, including the discovery of the regulatory oxysterol sulfate, its biosynthetic pathway, and its functional mechanism. We also propose that oxysterol sulfation functions as a regulatory signaling pathway. oxysterol sulfate; nuclear receptor; cholesterol and triglyceride metabolism;