Endocrine Abstracts

The peroxisome proliferator-activated receptors (PPARs) display a high degree of conservation in the DNA- and ligand-binding domains. Despite these sequence similarities, the PPARs show distinct functions, even when co-expressed. Many experimental approaches have been employed to determine the molecular mechanisms that underlie their subtype-specific characteristics. However, these approaches have largely relied on cell population based studies, such as ChIP-seq. Here we have ...

Synthetic glucocorticoids bind to the glucocorticoid receptor (GR) and have been used for nearly 70 years to treat inflammatory diseases. However, their use is limited by adverse effects such as diabetes, muscle wasting and osteoporosis. High throughput screening identified a novel non-steroidal scaffold with great potential for chemical optimization. Through rational design we developed the indazole ether series which combines high potency with structural motifs that provide ...

Castrate Resistant Prostate Cancer (CRPC) is the inevitable outcome of hormone treatment for advanced disease. Although no longer dependent on high levels of androgens, the androgen receptor (AR) remains active and there is evidence that other nuclear receptors (NRs) can drive CRPC progression and/or therapy resistance. NRs share a repertoire of essential coregulators: proteins possessing the ability to aid or repress NR action and have been proposed as a potential mechanism f...

Systemic lupus erythematosus (SLE) is a disease that disproportionately affects females. We previously showed that a functional knockout of estrogen receptor alpha (ERαKO) resulted in significantly reduced renal disease and increased survival in murine lupus. The mechanism of this effect, which requires estrogen, is not known. Interestingly, an ERα−/− (null mutant) mouse is not similarly protected. We and others have demonstrated a role for ERα in de...

Early-stage ER+ breast cancer (BC) with high tumor glucocorticoid receptor (GR) expression is associated with improved long term relapse-free survival compared to tumors with low GR expression. In addition, GR activity inhibits ER-mediated BC cell proliferation. We therefore hypothesized that GR and ER engage in nuclear receptor crosstalk to influence pro-proliferative gene expression, thus contributing to a better outcome in ER+/GR+ breast cancer. To understand the mechanisms...

Endometrial cancer (EC) is the most common gynaecological malignancy. Obesity is a major risk factor for EC and is associated with elevated cholesterol. 27-Hydroxycholesterol (27HC) is a cholesterol metabolite that functions as an endogenous agonist for Liver X Receptor (LXR) and a selective estrogen receptor modulator (SERM). Exposure to estrogenic ligands increases risk of developing EC however the impact of 27HC on EC is unknown.Samples of stage 1 EC ...

The retinoic acid receptor gamma (RARg, encoded by NR1B3/RARG) is significantly downregulated but not mutated in the MSKCC and PRAD prostate cancer (PCa) cohorts in the Cancer Genome Atlas (TCGA) data. We investigated the consequences of modifying RARg expression.Independent of ligand, stable RARg knockdown stimulated RWPE-1 and LNCaP cells proliferation, changed the cell cycle profile and significantly altered global gene expression patterns th...