Androgen Receptor in Prostate Cancer

Heinlein, Cynthia A.; Chang, Chawnshang

doi:10.1210/er.2002-0032

Cited by 1,511 publications

(1,448 citation statements)

References 351 publications

(282 reference statements)

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“…That may mean that distant metastasis was actually the cause of death. AR plays an important role in the development of prostate cancer and can be observed in primary prostate cancer and detected throughout the progression of both hormone-sensitive and hormone-refractory cancers [20,21]. In this study, AR expression was reduced in epithelial and stromal cells 1-week postcastration, which was the normal short-term response to castration in TRAMP mice.…”

Section: Discussionsupporting

confidence: 46%

Early and delayed castrations confer a similar survival advantage in TRAMP mice

Zhang¹,

Xu²,

Huang³

et al. 2009

Asian J Androl

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The most appropriate time to introduce androgen deprivation therapy for prostate cancer remains controversial. Our aim was to evaluate the effects of early versus delayed surgical castration on prostate cancer progression and survival in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. TRAMP mice were randomly divided into three groups: the early castration group (on which castration was performed at the age of 4 weeks), the delayed castration group (on which castration was performed when abdominal tumours could be palpated), and the sham-castrated group. Mice were monitored daily throughout their lives until cancer-related death or the development of an obviously moribund appearance, at which time the individual mouse was killed. Androgen receptor expression in prostate tumours was also evaluated. The results shows that the average lifespan in early castration, delayed castration and sham-castrated groups were 54.1 weeks, 59.9 weeks and 39.1 weeks, respectively. Both early castration and delayed castration conferred a statistically significant survival advantage when compared with the sham-castrated group (P < 0.001). However, the difference in lifespan between the early castration group and the delayed castration group was not statistically significant (P = 0.85). The increase in lifespan in the TRAMP mice that received either early or delayed castration correlated with lower G/B value (genitourinary tract weight/body weight) at death than the sham-castrated mice. In conclusion, early and delayed castrations in TRAMP mice prolonged survival to a similar extent. This finding may provide a guide for clinical practice in prostate cancer therapy.

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Section: Discussionsupporting

confidence: 46%

Early and delayed castrations confer a similar survival advantage in TRAMP mice

Zhang¹,

Xu²,

Huang³

et al. 2009

Asian J Androl

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“…Currently, it is not clear how precisely androgen induces AR nuclear translocation. Once the AR is in the nucleus, it will assemble a mega-protein transcription complex, which is a dynamic process including transient recruitment and then dissociation of co-factors, chromatin remodeling molecules, proteasome subunits and general transcription machinery (reviewed in Heinlein and Chang, 2004). We recently showed that PI3K inhibitors could not block AR nuclear translocation but suppressed AR-mediated gene expression (Liao et al, 2004), indicating that a PI3K-dependent mechanism is involved in AR-DNA binding, or the assembly of AR-mediated transcription complex.…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

et al. 2008

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Phosphoinositide 3-OH kinases (PI3Ks) are a group of major intracellular signaling molecules. In our previous study, we found that inhibition of PI3K activity suppressed the androgen receptor (AR)-mediated gene expression in prostate cancer cells. The AR has been considered as a critical determinant for the development and progression of human prostate cancers. In this study, we sought to identify the PI3K isoforms involved in AR transactivation. Using a gene-specific small interference RNA (siRNA) approach, we determined that the regulatory isoform p85a and the catalytic isoform p110b, but not p110a, were required for androgen-stimulated AR transactivation and cell proliferation in prostate cancer cells. Consistently, overexpression of wild-type p110b but not p110a gene led to androgen-independent AR transactivation. Silencing p110b gene in prostate cancer cells abolished tumor growth in nude mice. Of the dual (lipid and protein) kinase activities, p110b's lipid kinase activity was required for AR transactivation. Further analysis by a chromatin immunoprecipitation assay showed that p110b is indispensable for androgen-induced AR-DNA interaction. Finally, gene expression analysis of clinical specimens showed that both p85a and p110b were highly expressed in malignant prostate tissues compared to the nonmalignant compartments, and their expression levels correlated significantly with disease progression. Taken together, our data demonstrated that p85a and p110b are essential for androgen-stimulated AR transactivation, and their aberrant expression or activation might play an important role in prostate cancer progression.

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“…The loss of expression of VEGF has been proposed to lead to decreased vasculature, resulting in apoptosis of the luminal cells. 13 Although the initial response to androgen ablation is encouraging, resulting in apoptotic cell death and PCA regression, it is followed by development of aggressive HR disease. This process may vary in the length of time, ranging from a few months to 2 or 3 years.…”

Section: Androgens Maintain and Stimulate The Prostate Glandmentioning

confidence: 99%

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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Androgen Receptor in Prostate Cancer

Cited by 1,511 publications

References 351 publications

Early and delayed castrations confer a similar survival advantage in TRAMP mice

Early and delayed castrations confer a similar survival advantage in TRAMP mice

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

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

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