Mutation of the Androgen-Receptor Gene in Metastatic Androgen-Independent Prostate Cancer

Taplin, Mary‐Ellen; Bubley, Glenn J.; Shuster, Todd D.; Frantz, Martha E.; Spooner, Amy E.; Ogata, George K.; Keer, Harold; Balk, Steven P.

doi:10.1056/nejm199505253322101

Cited by 1,119 publications

(719 citation statements)

References 27 publications

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“…Tumour cells with mutations of the AR gene may enable transactivation of the AR by other steroids than the usual ligand dihydrotestosterone. 2,18 Furthermore, we recently found ampli®cation of the AR gene in about one third of tumours recurring during androgen deprivation. 19 The ®nding in the present study that recurrent tumours with AR ampli®cation were more highly proliferative, and more often aneuploid than their counterparts with no AR ampli®cation supports the signi®cance of AR gene ampli®cation in tumour recurrence and endocrine therapy failure.…”

Section: Discussionmentioning

confidence: 99%

Aneuploidy and rapid cell proliferation in recurrent prostate cancers with androgen receptor gene amplification

Koivisto

1997

Prostate Cancer Prostatic Dis

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Mechanisms of prostate cancer recurrence during androgen deprivation are poorly understood. We recently described androgen receptor (AR) gene ampli®-cation in 28% of recurrent prostate carcinomas from hormone-refractory prostate cancer patients. To investigate the hypothesis that ampli®cation of the AR gene promotes the growth of hormone-refractory prostate carcinomas, DNA¯ow cytometric (FCM) studies were carried out to compare matched, primary and hormone-refractory recurrent samples from 31 prostate cancer patients. Recurrent tumours had a higher (P 0.05) S-phase fraction (SPF) (10.6 AE 4.6) than corresponding primary tumours from the same patients (7.0 AE 4.1) and the frequency of aneuploidy also increased from 8±55%. Recurrent tumours with AR gene ampli®cation had a signi®cantly higher (P 0.02) SPF (14.0 AE 6.5) than those with no ampli®cation (9.0 AE 2.9). The results suggest that clinical progression of prostate cancer during androgen withdrawal therapy is often associated with increased cell proliferation rate and formation of DNA aneuploidy. AR ampli®-cation may be an important molecular mechanism underlying the increase in proliferation rate of some recurrent tumours.

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Section: Discussionmentioning

confidence: 99%

Aneuploidy and rapid cell proliferation in recurrent prostate cancers with androgen receptor gene amplification

Koivisto

1997

Prostate Cancer Prostatic Dis

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“…Mutations have been widely reported in 10-50% of recurring cancers. [29][30][31][32] However, the percentage of cases with AR mutations is probably lower and more on the order of o10% when all cases are taken into account. The majority of mutations reported map to the LBD.…”

Section: Amplification Of the Armentioning

confidence: 99%

“…Similar mutations in the same region have been reported. 29,30,[39][40][41] The type of treatment given was also shown to influence the kind of mutation seen. 42 Since reports have shown that mutations are present in 20-40% of the advanced PCAs before therapy, 30,31 it could be hypothesized that the mutations were not induced by therapy but were pre-existent.…”

Section: Amplification Of the Armentioning

confidence: 99%

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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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“…1 Although such 'total androgen blockage' can induce tumor regression, the effect is often short-lived. It has been suggested that genetic changes of the androgen receptor (AR) may contribute to a poor response to hormone therapy; 2,3 however, the mechanisms responsible for androgenindependence remain uncharacterized.…”

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confidence: 99%

Antiandrogens fail to block androstenedione‐mediated mutated androgen receptor transactivation in human prostate cancer cells

Miyamoto

Chang

2000

Int J of Urology

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Mutation of the Androgen-Receptor Gene in Metastatic Androgen-Independent Prostate Cancer

Abstract: Most metastatic androgen-independent prostate cancers express high levels of androgen-receptor gene transcripts. Mutations in androgen-receptor genes are not uncommon and may provide a selective growth advantage after androgen ablation.

Cited by 1,119 publications

References 27 publications

Aneuploidy and rapid cell proliferation in recurrent prostate cancers with androgen receptor gene amplification

Aneuploidy and rapid cell proliferation in recurrent prostate cancers with androgen receptor gene amplification

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

Antiandrogens fail to block androstenedione‐mediated mutated androgen receptor transactivation in human prostate cancer cells

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