Endocrine Abstracts

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...

A key mechanism of persistent cell survival under testosterone suppression in advanced prostate cancer (PC) is continued Androgen Receptor (AR) activation. This results from AR mutation, overexpression, hyper-activation, and/or expression of constitutively-active AR transcript variants (AR-Vs). AR has an unusually long 3’ untranslated region (3’UTR), which performs vital regulatory roles but is remarkably understudied. Its contribution to continued AR activation unde...

Prostate cancer is an androgen dependent malignancy that initially responds well to androgen ablation therapy. However treatment, castrate resistant prostate cancer eventually emerges. Even in that phase of the disease, the androgen receptor (AR) still seems to play a role. MicroRNAs are small (19–25nt) non-coding RNAs that modulate gene silencing through inhibition of translation and mRNA degradation. They are considered to be master regulators of gene expression and act...

Androgens are required for normal development and fertility. They have a vital role in tissues such as the reproductive tract, the brain, muscle and bone. Prostate cancer (PCa) is the most prevalent malignancy in western males: it is dependent upon circulating androgens and the therapies currently available aim to reduce synthesis of circulating androgens and/or inhibit the pathway using antiandrogens. Therapies inhibiting androgen signalling, and in particular the androgen re...

Defects in any of the four functional domains of the androgen receptor (AR) (resulting from loss-of-function or gain-of-function mutations), may affect androgen action. Specific AR splice variants have been reported in women with PCOS (Wang et al, PNAS 2015 112 4743). In this study we sought to identify AR splice variants in granulosa-lutein (GL) cells of women with and without PCOS and to assess their functional significance. GL cells were ...

Introduction: The importance of the liver-X receptors (LXRs) in the maintenance of cholesterol homeostasis within the testis has yet to be fully characterised. By 7 months of age, Lxrα/β double knockout male mouse (Lxrα/β DKO) develops sterility with aberrations in testosterone production and lipid homeostasis. However, the underlying testicular LXR-regulated pathways are not well understood.Aim: The aim of this study was to further u...

Prostate cancer often develops anti-androgen resistance, possibly via AR mutations which change AR antagonists to agonists. There is an urgent need for novel therapies which ideally show increased anticancer activity, whilst overcoming current drug resistance. Enobosarm has anabolic effects on muscle and bone tissues whilst having no effect on the prostate – often used to combat cachexia in advanced lung cancer. Here we describe the activity of novel chemically modified E...

Prostate cancer is currently treated with hormonal therapies, which aim to block the production and/or action of androgens. However, tumours eventually progress to castration-resistant prostate cancer and there is a great need for new therapeutic approaches. We have designed and tested engineered repressors which could be effective in circumstances where current therapies fail. These consist of two modules: an interaction domain, which binds directly to the androgen receptor (...

Introduction: LXRs are transcription factors that regulate cholesterol homeostasis and likely modulate other aspects of lipid metabolism. In the testis, tightly regulated lipid metabolism is crucial to maintain fertility. Testicular LXRs are highly expressed but their role in regulating lipid homeostasis is not fully understood. Lxrα/β double knockout male mice (Lxrα/β DKO) are sterile by 7 months of age, with aberrations in lipid...

Prostate Cancer (PC) affects 1-in-6 men in the UK, and obesity 1-in-3, with rates of both increasing. High-fat diet is linked with increased risk of PC death, and volume of peri-prostatic adipose tissue (PPAT) is associated with increased risk of lethal PC/reduced therapy response. Despite this, molecular mechanisms underpinning obesity-driven PC remain poorly-understood. This is important since weight-gain and central obesity are major side-effects of PC trea...