Retraction Note: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer.

This paper has been retracted at the request of the authors.

Histoplasmosis: An oral malignancy-like clinical picture.

HIV-associated histoplasmosis is mainly misdiagnosed for granulomatous diseases, such as tuberculosis. Nonetheless, malignancy-like lesions have been reported sporadically in HIV-infected patients. Although the main reported lesions are erosive or ulcerated, here a rare case of oral tumor is reported. This case raises the awareness of this presentation, and the importance of accurate identification in the laboratory. Performing systematic specific stains for fungal elements and culture on tissue samples ensures accurate differential diagnosis.

Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer.

Advanced prostate cancer (PCa) is a clinical challenge as no curative therapeutic is available. In this context, a better understanding of metastasis and resistance mechanisms in PCa is an important issue. As phosphatase and tensin homolog (PTEN) loss is the most common genetic lesion in such cancer, we investigate human data sets for mechanisms that can constrain cancer evolution in this setting. Here we report a liver X receptor (LXR) signature, which tightly correlates with PTEN loss, in PCa. Accordingly, the LXR pathway is deregulated in prostate carcinomas in Pten-null mice. Genetic ablation of LXRs in Pten-null mice, exacerbates PCa invasiveness and metastatic dissemination, which involves mesenchymal transition and accumulation of matrix metalloproteinases. Mechanistically, PTEN deletion governed LXR transcriptional activity through deregulation of cholesterol de novo synthesis, resulting in accumulation of endogenous LXR ligands. Our study therefore reveals a functional circuit linking PTEN and LXR, and highlights LXRs as metabolic gatekeepers that are able to constrain PCa progression.Treatment of prostate cancer, especially in its advanced stage, is still challenging; therefore, strategies to prevent metastatic dissemination are of great interest. Here the authors reveal a crucial role for liver X receptors in suppressing prostate carcinogenesis and metastatic progression in PTEN-null tumors.

Oxysterol receptors and their therapeutic applications in cancer conditions.

INTRODUCTION: Oxysterols are implicated in various cellular processes. Among their target proteins, liver X receptors (LXRs) α and ß modulate the cell cycle in a large range of cancer cell lines. Besides their role as cholesterol sensors, LXRs are also involved in the proliferation/apoptosis balance regulation in various types of cancers. AREAS COVERED: This review covers oxysterols and derivatives of cholesterol as well as synthetic or natural ligands (agonist/antagonist) of LXRs. Most tumor cell lines are sensitive to LXR activation. Indeed various cancers are concerned such as prostate, breast, glioblastoma, colorectal, and ovary tumors, and leukemia. EXPERT OPINION: Developing the use of LXR ligands in human health, especially in the field of cancer, represents a novel and promising strategy. Despite a wide spectrum of applications, numerous adverse effects of LXR activation need to be solved before genuine clinical trials in humans. Future directions will be based on the engineering of selective LXRs modulators (SLiMs) as already done for nuclear steroid receptors.

Liver x receptors protect from development of prostatic intra-epithelial neoplasia in mice.

LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux. LXR signaling is known to influence proliferation of different cell types including human prostatic carcinoma (PCa) cell lines. This study shows that deletion of LXR in mouse fed a high-cholesterol diet recapitulates initial steps of PCa development. Elevation of circulating cholesterol in Lxrαß-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia. This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions. Altogether, our data provide a novel link between LXR, cholesterol homeostasis, and epigenetic control of tumor suppressor gene expression.

Lack of liver X receptors leads to cell proliferation in a model of mouse dorsal prostate epithelial cell.

Recent studies underline the implication of Liver X Receptors (LXRs) in several prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer. In order to understand the molecular mechanisms involved, we derived epithelial cells from dorsal prostate (MPECs) of wild type (WT) or Lxrαß-/- mice. In the WT MPECs, our results show that LXR activation reduces proliferation and correlates with the modification of the AKT-survival pathway. Moreover, LXRs regulate lipid homeostasis with the regulation of Abca1, Abcg1 and Idol, and, in a lesser extent, Srebp1, Fas and Acc. Conversely cells derived from Lxrαß-/- mice show a higher basal phosphorylation and consequently activation of the survival/proliferation transduction pathways AKT and MAPK. Altogether, our data point out that the cell model we developed allows deciphering the molecular mechanisms inducing the cell cycle arrest. Besides, we show that activated LXRs regulate AKT and MAPK transduction pathways and demonstrate that LXRs could be good pharmacological targets in prostate disease such as cancer.

LXR, prostate cancer and cholesterol: the Good, the Bad and the Ugly.

Cholesterol is a fundamental molecule for life. Located in the cell membrane, this sterol participates to the cell signaling of growth factors. Inside the cell it can be converted in hormones such as androgens or modulate the immune response. Such important functions could not be solely dependent of external supply by diet hence de novo synthesis could occur from acetate in almost all mammalian cells. If a deficiency in cholesterol sourcing leads to development troubles, overstocking has been associated to various diseases such as atherosclerosis and cancers. Cholesterol homeostasis should thus be tightly regulated at the uptake, de novo synthesis, storage and export processes. Various transcription factors have been described these last years as important to regulate cholesterol levels. Besides, synthetic molecules have been developed for many years to modulate cholesterol synthesis, such as statins. Many articles have associated prostate cancer, whose incidence is constantly increasing, to cholesterol disequilibrium. Targeting cholesterol could thus be a new pharmacological hit to counteract the initiation, development and/or progression of prostate cancer. Among the transcription factors regulating cholesterol homeostasis, the nuclear receptors Liver X Receptors (LXRs) control cholesterol uptake and export. Targeting the LXRs offers a new field of investigation to treat cancer. This review highlights the molecular relationships among LXRs, prostate cancer and cholesterol and why LXRs have good chance to be targeted one day in this tumor. LXRs, prostate cancer and cholesterol, more than a "Ménage à trois", The Good, the Bad and the Ugly.

Oxysterol receptors, AKT and prostate cancer.

Oxysterols derive from cholesterol oxidation. They display various biological activities such as regulating cholesterol, fatty acid and glucose homeostasis as well as cell survival/apoptosis balance. Oxysterols display these metabolic and transcriptional activities mainly through their nuclear receptors known as Liver X Receptors (LXRs) α and ß. There is accumulating evidence that LXRs are key modulators of prostate cancer cell survival. Hence, LXR activation increases cholesterol efflux and induces a disruption of lipid rafts. The decrease of membrane cholesterol causes a down regulation of AKT survival pathway and consequently apoptosis. Moreover cholesterol is associated with an increased risk of developing aggressive forms of prostate cancer. These data highlight the interest of targeting the LXR-AKT axis in prostate carcinogenesis.

Lxrα regulates the androgen response in prostate epithelium.

Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.

Selective liver X receptor modulators (SLiMs): what use in human health?

Liver X receptors (LXR) are members of the nuclear receptor family. As activated transcription factors, their putative association with human diseases makes them promising pharmacological targets because of the large potential to develop ligands. LXR are mainly considered as intracellular cholesterol "sensors" whose activation leads to decreased plasma cholesterol. They also modulate numerous physiological functions: fatty acid synthesis and metabolism, glucose homeostasis, steroidogenesis, immunity, and neurological homeostasis. LXR-deficiency in mouse results in several phenotypes mimicking pathological conditions in humans. This review will be focused on the various natural and synthetic LXR agonists and antagonists. Putative clinical targets including atherosclerosis, diabetes, Alzheimer's disease, skin disorders, and cancer will be covered.

Targeting liver X receptors in human health: deadlock or promising trail?

INTRODUCTION: Liver X receptors (LXR) are transcription factors that belong to the nuclear receptor superfamily. Natural derivatives of cholesterol, known as oxysterols, have been identified as agonistic ligands of LXR. They are thus mainly considered to be intracellular cholesterol 'sensors' whose activation leads to decreased plasma cholesterol. Their implication in other physiologic processes currently prevents their use as therapeutic targets, because of potentially deleterious side effects. AREAS COVERED: The various LXR agonists and antagonists, along with the physiological functions of LXR. Putative clinical targets including atherosclerosis, diabetes, Alzheimer's disease, skin disorders, reproductive disorders and cancer. EXPERT OPINION: LXR are promising pharmacological targets because of the high potential to develop ligands owing to the variety of natural or synthetic agonists. Three aspects should be developed to select a LXR-ligand for treatment of human disease: bio-availability; isoform specificity; tissue specificity. This will allow the development of selective liver X modulators (SLiMs). The challenge is to overcome deleterious side effects to establish LXR as new pharmacological targets.