Androgen receptor gene mutations in hormone‐refractory prostate cancer

Wallén, Mika J.; Linja, Marika J.; Kaartinen, Kaius; Schleutker, Johanna; Visakorpi, Tapio

doi:10.1002/(sici)1096-9896(199912)189:4<559::aid-path471>3.3.co;2-p

Cited by 25 publications

(31 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[29][30][31] It is generally believed that the relatively infrequent mutations cannot account alone for the incidence of HR cancer. 31,43 The Role of Alternate Pathways…”

Section: Amplification Of the Armentioning

confidence: 99%

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Rubin

2008

Modern Pathology

View full text Add to dashboard Cite

The clinical dilemma today in the management of prostate cancer (PCA) is to distinguish men who need definitive treatment from men who have indolent disease. As demonstrated most recently by the randomized Scandinavian trial evaluating the benefit of prostatectomy over Watchful Waiting, surgery significantly decreased the risk of death from PCA. However, this same study also suggests that 19 men need to be treated to benefit one man. Given the high prevalence of the disease, the aging of the population, and the potential morbidity of treatment, the ability to distinguish aggressive from indolent forms of PCA is critical. Treatment for advanced PCA begins with androgen ablation, but eventually hormone-refractory (HR) PCA emerges. Novel therapies are in various stages of clinical trials, including kinase inhibitors, antisense oligonucleotides, and inhibitors of heat-shock proteins. The discovery of novel therapeutic approaches is an active area of clinical research. Eliminating HR PCA before it advances is a high priority in the biomarker field. Therefore, the development of molecular signatures of lethal PCA are critical. In addition, the recent discovery that a significant percentage of PCAs harbor a TMPRSS2-ETS gene fusion suggests that targeting either the ETS transcription factors or the fusion product may offer a novel approach to therapy. However, in 2007, the mainstay of treatment for advanced PCA remains androgen ablation therapy as originally introduced in the early 1940s.

show abstract

“…[29][30][31] It is generally believed that the relatively infrequent mutations cannot account alone for the incidence of HR cancer. 31,43 The Role of Alternate Pathways…”

Section: Amplification Of the Armentioning

confidence: 99%

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Rubin

2008

Modern Pathology

View full text Add to dashboard Cite

show abstract

“…First, androgen ablation results in changes in ligand specificity and/ or sensitivity followed by the activation of AR under low levels of androgens or antiandrogens [9,10]. In addition, ~30% of androgen-independent tumours have AR gene amplification that leads to androgen hypersensitivity [11]. Altered expression of AR coregulators may facilitate AR transactivation even at low levels of androgens [12].…”

Section: Introductionmentioning

confidence: 99%

Transgelin induces apoptosis of human prostate LNCaP cells through its interaction with p53

Zhang¹,

Yang²,

Zheng³

et al. 2010

Asian J Androl

View full text Add to dashboard Cite

The androgen receptor (AR) and its coregulators have important roles in the carcinogenesis of prostate cancer. p53 is an important tumour suppressor gene, and the absence of a fundamental p53 response may predispose to cancer. Transgelin, known as an ARA54-associated AR inhibitor, can suppress AR function in LNCaP cells. In addition to these effects, we aimed to elucidate the proapoptotic effects of the protein on LNCaP and its underlying mechanisms, especially the interaction between transgelin and p53. Cell counting, flow cytometric analysis and terminal deoxynucleotidyl transferase-dUTP nick-end labelling assays were applied to measure the proapoptotic effect of transgelin. Using western blotting of p53 and double immunofluorescence staining of p53 with transgelin, we show that transfection of transgelin results in increasing cytoplasmic translocation of p53 and upregulation of p53 expression. We also found an interaction between transgelin and p53 in vivo by mammalian two-hybrid and coimmunoprecipitation assays. The activation of the mitochondria-associated apoptosis pathway was observed in LNCaP cells after transfection with transgelin. These results are indicative of p53-mediated mitochondria-associated apoptotic effects of transgelin on LNCaP cells in addition to its known suppressive effects on the AR pathway.

show abstract

“…AR gene mutations In CRPC, AR mutations have been reported to occur at a frequency of 5-30% in pretreated tumors (Taplin et al 1999, Wallen et al 1999, Grasso et al 2012, Beltran et al 2013, Robinson et al 2015, Kumar et al 2016, CTCs (Jiang et al 2010) and ctDNA (Azad et al 2015, Lallous et al 2016. Although infrequent, AR mutations have also been detected in primary PCa prior to ADT or arising during treatment, and there is evidence that therapy-mediated selection of such mutations can underlie resistance in some patients (Tilley et al 1996, Taplin et al 1999, Thompson et al 2003, Steinkamp et al 2009, Carreira et al 2014, Cancer Genome Atlas Research 2015.…”

Section: Ar Overexpressionmentioning

confidence: 99%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

148

122

View full text Add to dashboard Cite

The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

show abstract

Androgen receptor gene mutations in hormone‐refractory prostate cancer

Cited by 25 publications

References 0 publications

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Transgelin induces apoptosis of human prostate LNCaP cells through its interaction with p53

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Contact Info

Product

Resources

About