Searchable abstracts of presentations at key conferences in endocrinology
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Androgens 2016

ea0042oc1 | (1) | Androgens2016

Non-classical testosterone signaling in the testis

Dietze Raimund , Bulldan Ahmed , Shihan Mazen , Chan Kai-Hui , Konrad Lutz , Scheiner-Bobis Georgios

Although classical and non-classical signaling of testosterone (T) has been observed in the testis, the enigma of the non-classical pathway is not fully resolved. While some researchers favor the androgen receptor (AR), others propose a membrane-bound receptor for non-classical T signaling. Although silencing of the AR in Sertoli cells (SC) resulted in infertility and suggested no involvement of the non-classical pathway, recent experiments using an inhibitor of the non-classi...

ea0042oc2 | (1) | Androgens2016

Control of androgen bioactivity by sex hormone-binding globulin

Laurent Michael R , Antonio Leen , Blokland Marco H , Sterk Saskia S , Jardi Ferran , Dubois V , Kaufman Jean-Mark , Fiers Tom , Huhtaniemi Ilpo T , Hammond Geoffrey T. , Vanderschueren Dirk , Claessens Frank

Sex hormone-binding globulin (SHBG) is a high-affinity binding protein for androgens and estrogens. According to the “free hormone hypothesis”, SHBG regulates the free sex steroid fraction and restricts androgen bioactivity. SHBG has also been independently associated with diabetes, osteoporosis etc., but whether this represents causality or residual confounding remains unconfirmed. We studied mice overexpressing human SHBG. Using multiligand liquid chromatography ta...

ea0042oc3 | (1) | Androgens2016

Novel trifluoromethylated enobosarm analogues show very potent antiandrogen activity in prostate cancer cells, and cells with acquired bicalutamide resistance whilst maintaining tissue selectivity in vivo

Dart Alwyn , Kandil Sahar , Tommasini-Ghelfi Serena , Bevan Charlotte , Jiang Wenguo , Westwell Andrew D.

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...

ea0042oc4 | (1) | Androgens2016

The use of apolipoprotein D as a biomarker for androgen sensitivity identifies a new type of androgen insensitivity syndrome that is not associated with a mutation in the androgen receptor gene

Hornig Nadine C , Ukat Martine , Schweikert Hans-Udo , Hiort Olaf , Werner Ralf , Drop Stenvert LS , Cools Martine , Hughes Ieuan A , Audi Laura , Ahmed S Faisal , Demiri Jeta , Rodens Pascal , Worch Lisa , Wehner Gaby , Kulle Alexandra E , Dunstheimer Desiree , Muller-Roszberg Elke , Reinehr Thomas , Hadidi Ahmed T , Eckstein Anne K , van der Horst Christof , Seif Christoph , Siebert Reiner , Ammerpohl Ole , Holterhus Paul-Martin

Although androgen insensitivity syndrome (AIS) is commonly suspected as a cause of a 46,XY disorder of sex development (DSD), only about half of these cases can be attributed to an inactivating mutation within the coding sequence (CDS) of the androgen receptor (AR) gene. This led to the hypothesis that disrupted AR activation in AIS may also be caused by a defect in a co-factor of AR-activity. However, so far mutations in AR co-factors leading to AIS have not been ide...

ea0042oc5 | (1) | Androgens2016

What is the impact of AR modulation in the decidualisation of hESCs from women with endometriosis?

Simitsidellis Ioannis , Gibson Douglas A. , Kelepouri Olympia , Horne Andrew W. , Saunders Philippa T. K.

Endometriosis is a hormone-dependent disorder, characterised by growth of endometrial tissue outside the uterus. It has been reported that 30–40% of women with infertility have endometriosis. Transformation of human endometrial stromal fibroblasts (hESC) (termed decidualisation) is accompanied by increased steroid synthesis and is fundamental to the establishment of a receptive endometrial microenvironment, which can support and maintain pregnancy. Evidence suggests that ...

ea0042oc6 | (1) | Androgens2016

Transgender: biological model for steroid action

Wildt Ludwig , Winkler-Crepaz Katharina , Boettcher Bettina

Transgender patients are treated by down-regulation oft he pituitary gland and the gonads with GnRH- analogues and the opposite male or female sex steroids, followed by gonadectomy. After gonadectomy, the GnRH analogue is discontinued while the treatment with sex steroids (estrogen or testosterone) is continued. This offers the unique possibility to study the effects of sex steroids on bone density, metabolism, and other regulatory systems in the opposite sex. We present data ...

ea0042oc7 | (1) | Androgens2016

Identification of AR genomic targets in mesenchymal cell subsets during prostate development

Nash Claire , Boufaied Nadia , Thomson Axel A.

Sexually dimorphic organogenesis of the prostate is a key function of androgens during mammalian development. Mesenchymal AR signalling is essential for prostate development, while epithelial AR is not required. Within the mesenchyme there are distinct mesenchymal subsets that show differential effects of androgens; androgens regulate the thickness of the urethral smooth muscle layer, while in the inductive mesenchymal pad, androgens stimulate branching and growth of prostate ...

ea0042oc8 | (1) | Androgens2016

Fibroblast AR signalling in prostate cancer: Unique regulation of AR signalling, and associations with patient outcomes by influencing cancer progression and invasion

Leach Damien A. , Need Eleanor F. , Buchanan Grant

The stromal compartment changes with cancer, with an emergence in activated fibroblasts. These stromal changes, which occur with cancer initiation and throughout progression, are known to influence the hallmarks of cancer and are becoming increasingly studied for prognostic and therapeutic purposes. Androgen receptor (AR) signalling in stromal cells is important in prostate cancer and these cancer stromal communications, yet the mechanisms underpinning stromal AR contribution ...

ea0042oc9 | (1) | Androgens2016

Chromatin relaxation is a feature of advanced prostate cancer

Urbanucci Alfonso , Barfeld Stefan , Kytola Ville , Vodak Daniel , Sjoblom Liisa , Tolonen Teemu , Minner Sarah , Burdelski Christoph , Kivinummi Kati K. , Kregel Steven , Takhar Mandeep , Alshalalfa Mohammed , Davicioni Elai , Erho Nicholas , Karnes R. Jeffrey , Ross Ashley E. , Schaeffer Edward M. , Vander Griend Donald J. , Knapp Stefan , Tammela Teuvo L.J. , Sauter Guido , Schlomm Thorsten , Nykter Matti , Visakorpi Tapio , Mills Ian G.

Epigenetic reprogramming including altered transcription factor binding and altered patterns of chromatin and DNA modifications are now accepted as the hallmark of aggressive cancers. We show that global changes in chromatin structure and chromatin accessibility in prostate tumour tissue can define castrate-resistant prostate cancer and be used to inform the discovery of gene-level classifiers for therapy. In addition, we show that the androgen receptor overexpression alone, w...

ea0042oc10 | (1) | Androgens2016

Glycosylation is a global target for androgen control in prostate cancer cells

Munkley Jennifer , Livermore Karen E. , Vodak Daniel , James Katherine , Wilson Brian T. , McClurg Urszula L. , Knight Bridget , MCcullagh Paul , Mcgrath John , Crundwell Malcolm , Harries Lorna W. , Leung Hing Y. , Robson Craig N. , Oltean Sebastian , Mills Ian G. , Rajan Prabhakar , Elliott David J.

Changes in glycan composition are common in cancer and can play important roles in all of the recognised hallmarks of cancer (1). We recently identified glycosylation as a global target for androgen control in prostate cancer cells and further defined a set of 8 glycosylation enzymes (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3), which are also significantly up-regulated in prostate cancer tissue (4). These 8 enzymes are under direct control of the and...

ea0042oc11 | (1) | Androgens2016

Sex steroid deficiency alters renal calcium transporter expression independently of its effect on bone resorption

Khalil Rougin , Jardi Ferran , Laurent Michael , Claessens Frank , Vanderschueren Dirk , Decallonne Brigitte

It is well established that sex steroid deficiency induces bone loss, resulting in osteoporosis. Consequently, global androgen receptor knock out (ARKO) mice have trabecular and cortical osteopenia. Bone cell-specific ARKOs however, have a much less pronounced bone phenotype, suggesting that androgens have an influence on processes in other systems or organs which in turn have an impact on bone metabolism. The kidney is a likely candidate, as it plays an important role in calc...

ea0042oc12 | (1) | Androgens2016

Rapid cycling high dose testosterone (Bipolar Androgen Therapy) as therapy for men with metastatic castrate-resistant prostate cancer (mCRPC)

Denmeade Samuel R. , Antonarakis Emmanuel , Paller Channing , Wang Hao , Teply Ben , Drake Charles , Carducci Michael , Luo Jun , Eisenberger Mario

Prostate cancer (PC) becomes resistant to chronic castration via an adaptive increase in androgen receptor (AR) axis activity. AR overexpression, however, is a liability that can be exploited therapeutically through rapid cycling between high supraphysiologic and low castrate levels of serum testosterone (T), (Bipolar Androgen Therapy (BAT)). In a pilot study, 14 men with CRPC treated with BAT showed a 50% PSA and objective response. A larger study was initiated in which asymp...

ea0042oc13 | (1) | Androgens2016

The role of nuclear steroid receptors in castration-resistant prostate cancer (CRPC)

Nowakowska Karolina , Riisnaes Ruth , Rodrigues Daniel Nava , Wetterskog Daniel , Jayaram Anuradha , Zaferiou Zafeiris , Mateo Joaquin , de Bono Johann S , Attard Gerhardt

With the wide-spread use of abiraterone/enzalutamide for CRPC, there is an urgent need to understand and reverse resistance to these treatments. Studies have implicated glucocorticoid receptor (GR) as activating androgen receptor (AR) signalling and driving resistance. Here we studied progesterone receptor (PR), which is phylogenetically most closely related to the AR. We first used digital droplet PCR in prostate cancer (PCa) cell lines and observed >10 times higher level...

ea0042oc14 | (1) | Androgens2016

Optimization of an engineered microrepressor for the treatment of castration-resistant prostate cancer

Fioretti Flavia Marialucia , Lai Chun Fui , Powell Sue , Ali Simak , Brooke Greg N. , Bevan Charlotte

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 (...

ea0042oc15 | (1) | Androgens2016

In vivo imaging reveals prostate pathology in the PTEN knockout murine model of prostate cancer

Bhatti Alysha , de Almeida Gilberto Serrano , Ghelfi Serena Tommasini , Dart Alwyn , Varela-Carver Anabel , Bevan Charlotte L.

Prostate cancer (PCa) is driven by the androgen receptor (AR) signalling axis and begins with prostatic intraepithelial neoplasia (PIN), progressing to invasive adenocarcinoma and eventually metastatic disease. It is treated with androgen deprivation therapies, to which, in late-stage disease, tumours often become resistant and proliferation occurs in a low androgen environment. Mutation of the PTEN tumour suppressor gene is found in approximately 30% of primary human prostate...

ea0042oc16 | (1) | Androgens2016

Genomic analysis of Enzalutamide-resistant cells

Prekovic Stefan , Van den Broeck Thomas , Smeets Elien , van Royen Martin , Houtsmuller Adriaan , Sahu Biswajyoti , Pihlajamaa Paivi , Janne Olli A. , Attard Gerhardt , Claessens Frank , Helsen Christine

Enzalutamide (Enza) is a second-generation antiandrogen currently used in the clinic for treatment of metastatic prostate cancer. It significantly prolonged survival of men with metastatic castration resistant prostate cancer after chemotherapy by a median of 4.8 months in comparison to the placebo group. However, in a subset of patient’s beneficial effect of Enza cannot be observed, while others who initially respond eventually develop resistance towards the treatment. U...

ea0042oc17 | (1) | Androgens2016

miR-32 promotes replicative changes in prostate epithelium in vivo

Latonen Leena , Gillen Andrew , Valkonen Mira , Ruusuvuori Pekka , Zhang Fuping , Poutanen Matti , Visakorpi Tapio

The androgen receptor (AR) signaling pathway is central to the emergence of castration-resistant prostate cancer (CRPC). miR-32 is an androgen regulated miRNA which is differentially expressed in CRPC compared to benign prostatic hyperplasia (BPH) and able to provide a significant growth advantage to LNCaP cells. To study how increased miR-32 expression contributes to prostate cancer formation and/or progression in vivo, we have established transgenic mice expressing ...