Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice.

Background: Regular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood.

Methods: We used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden.

Results: We show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression (MMTV-PyMT) mouse model of breast cancer but only when mice are not housed alone.

A tumour suppressive relationship between mineralocorticoid and retinoic acid receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer.

Background: The role of nuclear receptors in both the aetiology and treatment of breast cancer is exemplified by the use of the oestrogen receptor (ER) as a prognostic marker and treatment target. Treatments targeting the oestrogen signalling pathway are initially highly effective for most patients. However, for the breast cancers that fail to respond, or become resistant, to current endocrine treatments, the long-term outlook is poor.

The Alternative Splicing Regulator Nova2 Constrains Vascular Erk Signaling to Limit Specification of the Lymphatic Lineage.

The correct assignment of cell fate within fields of multipotent progenitors is essential for accurate tissue diversification. The first lymphatic vessels arise from pre-existing veins after venous endothelial cells become specified as lymphatic progenitors. Prox1 specifies lymphatic fate and labels these progenitors; however, the mechanisms restricting Prox1 expression and limiting the progenitor pool remain unknown.

Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies.

Breast cancer is a heterogeneous disease, and the complexity of breast carcinogenesis is associated with epigenetic modification. There are several major classes of epigenetic enzymes that regulate chromatin activity. This review will focus on the nine mammalian protein arginine methyltransferases (PRMTs) and the dysregulation of PRMT expression and function in breast cancer.

The Nuclear Receptor Nor-1 Is a Pleiotropic Regulator of Exercise-Induced Adaptations.

Exercise induces various physical and metabolic changes in skeletal muscle that adaptively reprograms this tissue to current physiological and environmental demands. Underlying these changes are broad modifications to gene expression. We postulate that the nuclear hormone receptor, Nor-1, is activated after exercise, and this transcription factor modifies gene expression to drive the molecular and cellular adaptations associated with contractile reorganization.

NFIB Mediates BRN2 Driven Melanoma Cell Migration and Invasion Through Regulation of EZH2 and MITF.

While invasion and metastasis of tumour cells are the principle factor responsible for cancer related deaths, the mechanisms governing the process remain poorly defined. Moreover, phenotypic divergence of sub-populations of tumour cells is known to underpin alternative behaviors linked to tumour progression such as proliferation, survival and invasion. In the context of melanoma, heterogeneity between two transcription factors, BRN2 and MITF, has been associated with phenotypic switching between predominantly invasive and proliferative behaviors respectively.

Therapeutic Implications of Epigenetic Signaling in Breast Cancer.

Breast cancer is a heterogeneous disease and its complexity has hindered the development of efficacious treatments targeting all breast cancer subtypes. Many studies have linked the diversity of breast carcinogenesis and metastasis to aberrant epigenetic signaling and control. Here, we focus on the current state of the discipline and review the major epigenetic enzymes controlling chromatin structure and function in the context of breast cancer, including (1) DNA methyltransferases, (2) lysine methyltransferases and demethylases, (3) protein arginine methyltransferases, and (4) histone acetyltransferases and deacetylases.

Transgenic Adipose-specific Expression of the Nuclear Receptor RORα Drives a Striking Shift in Fat Distribution and Impairs Glycemic Control.

RORα is a member of the nuclear receptor (NR) superfamily and analysis of the (global) RORα-deficient mouse model revealed this NR has a role in glycemic control and fat deposition. Therefore, we generated an adipose-specific RORα 'gain of function' mouse model under the control of the fatty acid binding protein 4 (FABP4) promoter to elucidate the function of RORα in adipose tissue. The Tg-FABP4-RORα4 mice demonstrated a shift in fat distribution to non-adipose tissues when challenged with a high fat diet (HFD).

The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis.

We have previously reported that RORγ expression was decreased in ER-ve breast cancer, and increased expression improves clinical outcomes. However, the underlying RORγ dependent mechanisms that repress breast carcinogenesis have not been elucidated. Here we report that RORγ negatively regulates the oncogenic TGF-β/EMT and mammary stem cell (MaSC) pathways, whereas RORγ positively regulates DNA-repair.

The Nuclear Receptor, Nor-1, Induces the Physiological Responses Associated With Exercise.

Skeletal muscle remodels metabolic capacity, contractile and exercise phenotype in response to physiological demands. This adaptive remodeling response to physical activity can ameliorate/prevent diseases associated with poor diet and lifestyle. Our previous work demonstrated that skeletal muscle-specific transgenic expression of the neuron-derived orphan nuclear receptor, Nor-1 drives muscle reprogramming, improves exercise endurance, and oxidative metabolism.

RORα and 25-Hydroxycholesterol Crosstalk Regulates Lipid Droplet Homeostasis in Macrophages.

Nuclear hormone receptors have important roles in the regulation of metabolic and inflammatory pathways. The retinoid-related orphan receptor alpha (Rorα)-deficient staggerer (sg/sg) mice display several phenotypes indicative of aberrant lipid metabolism, including dyslipidemia, and increased susceptibility to atherosclerosis. In this study we demonstrate that macrophages from sg/sg mice have increased ability to accumulate lipids and accordingly exhibit larger lipid droplets (LD).

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue.

The Rar-related orphan receptor-α (Rorα) is a nuclear receptor that regulates adiposity and is a potential regulator of energy homeostasis. We have demonstrated that the Rorα-deficient staggerer (sg/sg) mice display a lean and obesity-resistant phenotype. Adaptive Ucp1-dependent thermogenesis in beige/brite and brown adipose tissue serves as a mechanism to increase energy expenditure and resist obesity.

Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease.

Cumulative exposure to estrogen (E) and progesterone (P) over the menstrual cycle significantly influences the risk of developing breast cancer. Despite the dogma that PR in the breast merely serves as a marker of an active estrogen receptor (ER), and as an inhibitor of the proliferative actions of E, it is now clear that in the breast P increases proliferation independently of E action. We show here that the progesterone receptor (PR) and ER are expressed in different epithelial populations, and target non-overlapping pathways in the normal human breast.

PRMT2 and RORγ expression are associated with breast cancer survival outcomes.

Protein arginine methyltransferases (PRMTs) methylate arginine residues on histones and target transcription factors that play critical roles in many cellular processes, including gene transcription, mRNA splicing, proliferation, and differentiation. Recent studies have linked PRMT-dependent epigenetic marks and modifications to carcinogenesis and metastasis in cancer. However, the role of PRMT2-dependent signaling in breast cancer remains obscure.

Breast cancer prognosis predicted by nuclear receptor-coregulator networks.

Although molecular signatures based on transcript expression in breast cancer samples have provided new insights into breast cancer classification and prognosis, there are acknowledged limitations in current signatures. To provide rational, pathway-based signatures of disrupted physiology in cancer tissues that may be relevant to prognosis, this study has directly quantitated changed gene expression, between normal breast and cancer tissue, as a basis for signature development. The nuclear receptor (NR) family of transcription factors, and their coregulators, are fundamental regulators of every aspect of metazoan life, and were rigorously quantified in normal breast tissues and ERα positive and ERα negative breast cancers.

Nuclear receptor expression in human differentiated thyroid tumors.

Background: Nuclear receptors (NRs) play a key role in endocrine signaling and metabolism and are important therapeutic targets in a number of hormone-dependent malignancies. Studies on the role of NRs in thyroid cancer are limited.

Objective: The objective of the study was to examine systematically the expression of the 48 human NRs in a series of benign and malignant thyroid tissues.

The NR4A2 nuclear receptor is recruited to novel nuclear foci in response to UV irradiation and participates in nucleotide excision repair.

Ultraviolet radiation (UVR) is one of the most common mutagens encountered by humans and induces the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6-4)-pyrimidone photoproduct (6-4PP) lesions in the genomic DNA. To prevent the accumulation of deleterious mutations these lesions must be efficiently repaired, primarily by nucleotide excision repair. We have previously demonstrated that the NR4A family of nuclear receptors are crucial mediators of the DNA repair function of the MC1R signalling pathway in melanocytes.

Distinct nuclear receptor expression in stroma adjacent to breast tumors.

The interaction between breast tumor epithelial and stromal cells is vital for initial and recurrent tumor growth. While breast cancer-associated stromal cells provide a favorable environment for proliferation and metastasis, the molecular mechanisms contributing to this process are not fully understood. Nuclear receptors (NRs) are intracellular transcription factors that directly regulate gene expression.

Transgenic muscle-specific Nor-1 expression regulates multiple pathways that effect adiposity, metabolism, and endurance.

The mRNA encoding Nor-1/NR4A3 is rapidly and strikingly induced by β2-adrenergic signaling in glycolytic and oxidative skeletal muscle. In skeletal muscle cells, Nor-1 expression is important for the regulation of oxidative metabolism. Transgenic skeletal muscle-specific expression of activated Nor-1 resulted in the acquisition of an endurance phenotype, an increase in type IIA/X oxidative muscle fibers, and increased numbers of mitochondria.

Caveolin-1 is necessary for hepatic oxidative lipid metabolism: evidence for crosstalk between caveolin-1 and bile acid signaling.

Caveolae and caveolin-1 (CAV1) have been linked to several cellular functions. However, a model explaining their roles in mammalian tissues in vivo is lacking. Unbiased expression profiling in several tissues and cell types identified lipid metabolism as the main target affected by CAV1 deficiency.

Nuclear receptors and epigenetic signaling: novel regulators of glycogen metabolism in skeletal muscle.

Glycogen is an energy storage depot for the mammalian species. This review focuses on recent developments that have identified the role of nuclear hormone receptor (NR) signaling and epigenomic control in the regulation of important genes that modulate glycogen metabolism. Specifically, new studies have revealed that the NR4A subgroup (of the NR superfamily) are strikingly sensitive to beta-adrenergic stimulation in skeletal muscle, and transgenic studies in mice have revealed the expression of these NRs affects endurance and glycogen levels in muscle.

Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.

To identify biologically relevant groupings or clusters of nuclear receptors (NR) that are associated with breast neoplasia, with potentially diagnostic, discriminant or prognostic value, we quantitated mRNA expression levels of all 48 members of the human NR superfamily by TaqMan low-density array analysis in 116 curated breast tissue samples, including pre- and postmenopausal normal breast and both ERα(+) and ERα(-) tumor tissue. In addition, we have determined NR levels in independent cohorts of tamoxifen-treated ERα(+) and ERα(-) tissue samples. There were differences in relative NR mRNA expression between neoplastic and normal breast, and between ER(+) and ER(-) tumors.

Disruption of Rorα1 and cholesterol 25-hydroxylase expression attenuates phagocytosis in male Rorαsg/sg mice.

We and others have previously demonstrated that congenital deficiency of the nuclear hormone receptor, Rorα1, in staggerer (sg/sg) mice results in resistance to diet-induced obesity and increased insulin sensitivity. Paradoxically, the sg/sg mice are susceptible to atherosclerosis and display impaired innate immunity, underscoring the regulatory links between metabolic disease, inflammation, and susceptibility to infection. Here, we present novel evidence that Rorα1 regulates innate immune function by demonstrating impaired phagocytosis in sg/sg mice.

Orphan nuclear receptors and the regulation of nutrient metabolism: understanding obesity.

Nuclear hormone receptors (NRs) are a superfamily of eukaryotic ligand-dependent transcription factors that translate endocrine, metabolic, nutritional, developmental, and pathophysiological signals into gene regulation. Members of the NR superfamily (on the basis of sequence homology) that lack identified natural and/or synthetic ligands are/were classified as "orphan" NRs. These members of the NR superfamily are abundantly expressed in tissues associated with major metabolic activity, such as skeletal muscle, adipose, and liver.

Protein arginine methyltransferase 6-dependent gene expression and splicing: association with breast cancer outcomes.

Protein arginine methyltransferase-6 (PRMT6) regulates steroid-dependent transcription and alternative splicing and is implicated in endocrine system development and function, cell death, cell cycle, gene expression and cancer. Despite its role in these processes, little is known about its function and cellular targets in breast cancer. To identify novel gene targets regulated by PRMT6 in breast cancer cells, we used a combination of small interfering RNA and exon-specific microarray profiling in vitro coupled to in vivo validation in normal breast and primary human breast tumours.