Androgen Receptor Alterations in Prostate Cancer Relapsed during a Combined Androgen Blockade by Orchiectomy and Bicalutamide

Haapala, Kyllikki; Hyytinen, E.; Roiha, Mikko; Laurila, Marita; Rantala, Immo; Helin, Heikki; Koivisto, Pasi A.

doi:10.1038/labinvest.3780378

Cited by 94 publications

(55 citation statements)

References 15 publications

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“…16 Combined orchiectomy and bicalutamide treatment did not result in amplification. 27 Hence, all these observations further emphasize the involvement of other mechanisms apart from amplification involved in AR upregulation and transition into aggressive cancers.…”

Section: Amplification Of the Armentioning

confidence: 82%

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

Rubin

2008

Modern Pathology

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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.

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Section: Amplification Of the Armentioning

confidence: 82%

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

Rubin

2008

Modern Pathology

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“…48 -50 Recently, mutated ARs were detected in samples from patients whose tumors relapsed after a combined androgen blockade by orchiectomy and bicalutamide. 51 It is, however, not known whether those mutants are increasingly activated by bicalutamide.…”

Section: Discussionmentioning

confidence: 99%

The Transcriptional Co-Activator cAMP Response Element-Binding Protein-Binding Protein Is Expressed in Prostate Cancer and Enhances Androgen- and Anti-Androgen-Induced Androgen Receptor Function

Comuzzi¹,

Lambrinidis²,

Rogatsch³

et al. 2003

The American Journal of Pathology

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“…In tumours, several mechanisms have been involved in the unavoidable progression to androgen independency, by which tumour cells evolve to bypass the ligand-dependent regulation of AR. 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].…”

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

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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.

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Androgen Receptor Alterations in Prostate Cancer Relapsed during a Combined Androgen Blockade by Orchiectomy and Bicalutamide

Cited by 94 publications

References 15 publications

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

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

The Transcriptional Co-Activator cAMP Response Element-Binding Protein-Binding Protein Is Expressed in Prostate Cancer and Enhances Androgen- and Anti-Androgen-Induced Androgen Receptor Function

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

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