The liver X receptors (LXRs) are nuclear receptors that are activated by endogenous oxysterols, oxidized derivatives of cholesterol. There are two isoforms of LXR, LXRa (NR1H3) and LXRb (NR1H2). Both LXRa and LXRb regulate gene expression by binding to DNA sequences associated with target genes as heterodimers with isoforms of the retinoid X receptor (RXR), RXRa (NR2B1), RXRb (NR2B2), and RXRg (NR2B3). LXRs act as cholesterol sensors: when cellular oxysterols accumulate as a result of increasing concentrations of cholesterol, LXR induces the transcription of genes that protect cells from cholesterol overload. In this review, we summarize the roles of LXRs in controlling cholesterol homeostasis, including their roles in bile acid synthesis and metabolism/excretion, reverse cholesterol transport, cholesterol biosynthesis and uptake, and cholesterol absorption/excretion in the intestine. The overlapping and distinct roles of the LXRa and LXRb isoforms, and the potential use of LXRs as attractive targets for treatment of cardiovascular disease are also discussed.

The discovery of a second estrogen receptor (ER), designated ERβ (NR3A2), has redefined our knowledge about the mechanisms underlying cellular signaling by estrogens and has broad implications for our understanding of regulation of estrogen-responsive tissues. Highly variable and even contrasting effects of estrogens in different tissues seem to be at least partially explained by different estrogen signaling pathways, involving ERα (NR3A1) and/or ERβ. To date, two key conclusions can be drawn from the significant body of work carried out on the specific roles of the two receptor subtypes in diverse estrogen target tissues. First, ERα and ERβ have different biological functions, as indicated by their specific expression patterns and the distinct phenotypes observed in ERα and ERβ knockout (αERKO and βERKO) mice. Second, ERα and ERβ appear to have overlapping but also unique sets of downstream target genes, as judged from a set of microarray experiments. Thus, ERα and ERβ have different transcriptional activities in certain ligand, cell-type, and promoter contexts, which may help to explain some of the major differences in their tissue-specific biological actions. The phenotypes observed for βERKO mice have suggested certain therapeutic areas to be further explored. The development of ERβ-selective ligands active in animal disease models indicates new avenues for clinical exploration. ERβ agonists are being explored and validated as drugs for a growing number of indications. Hopefully, some ERβ targeted drugs will prove to be efficient in enhancing human health.

Estrogen receptor B (ERB) is the predominant ER in the colorectal epithelium. Compared with normal colon tissue, ERB expression is reduced in colorectal cancer. Our hypothesis is that ERB inhibits proliferation of colon cancer cells. Hence, the aim of this study has been to investigate the molecular function of ERB in colon cancer cells, focusing on cell cycle regulation. SW480 colon cancer cells have been lentivirus transduced with ERB expression construct with or without mutated DNA-binding domain or an empty control vector. Expression of ERB resulted in inhibition of proliferation and G 1 phase cell cycle arrest and this effect was dependent on a functional DNA-binding region. c-Myc is overexpressed in an overwhelming majority of colorectal tumors. By Western blot and real-time PCR, we found c-Myc to be down-regulated in the ERB-expressing cells. Furthermore, the c-Myc target gene p21 (Waf1/Cip1) was induced and Cdc25A was reduced by ERB at the transcriptional level. The second cdk2-inhibitor, p27 Kip1 , was induced by ERB, but this regulation occurred at the posttranscriptional level, probably through ERB-mediated repression of the F-box protein p45 Skp2 . Expression of the ERB-variant with mutated DNA binding domain resulted in completely different cell cycle gene regulation. We performed in vivo studies with SW480 cells F ERB transplanted into severe combined immunodeficient/beige mice; after three weeks of ERB-expression, a 70% reduction of tumor volume was seen. Our results show that ERB inhibits proliferation as well as colon cancer xenograft growth, probably as a consequence of ERB-mediated inhibition of cell-cycle pathways. Furthermore, this ERB-mediated cell cycle repression is dependent on functional ERE binding. [Cancer Res 2009;69(15):6100-6]

The metabolic syndrome is a complex condition characterized by obesity, insulin resistance, decreased high-density lipoproteins, and hypertension associated with high risk of developing type 2 diabetes and cardiovascular disease. A major increase in the incidence of developing metabolic syndrome and related diseases is observed worldwide in association with a change toward a less active lifestyle and increased food consumption. Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of metabolism, including glucose and lipid metabolism, and impaired estrogen signaling is associated with the development of metabolic diseases. This review will describe the key effects of estrogen signaling in metabolic and glucose sensing tissues, including the liver, pancreatic b cells, adipose tissue, and skeletal muscle. The impact on metabolic processes of impaired estrogen signaling and knock out of each ER subtype will also be discussed.

Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties. Cancer Res; 74(14); 3983-94. Ó2014 AACR.