In vivo amplification of the androgen receptor gene and progression of human prostate cancer

  title={In vivo amplification of the androgen receptor gene and progression of human prostate cancer},
  author={Tapio Visakorpi and Eija-R. Hyytinen and Pasi A. Koivisto and Minna M. Tanner and Riitta Keinänen and Christopher Palmberg and Aarno Palotie and Teuvo L.J. Tammela and Jorma Isola and Olli Kallioniemi},
  journal={Nature Genetics},
Overexpression of amplified genes is often associated with the acquisition of resistance to cancer therapeutic agents in vitro. We have identified a similar molecular mechanism in vivo for endocrine treatment failure in human prostate cancer which involves amplification of the androgen receptor (AR) gene. Comparative genomic hybridization shows that amplification of the Xq11–q13 region (the location), is common in tumours recurring during androgen deprivation therapy. We found high–level AR… 

Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer.

Failure of conventional androgen deprivation therapy in prostate cancer may be caused by a clonal expansion of tumor cells that are able to continue androgen-dependent growth despite of the low concentrations of serum androgens.

Androgen receptor gene amplification: a novel molecular mechanism for endocrine therapy resistance in human prostate cancer.

Discovery of AR amplification as a possible molecular mechanism of therapy resistance in prostate cancer should prove useful for development of more effective endocrine therapy regimens as well as diagnostic and predictive tests for therapy failure.

Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence.

The data indicate that AR gene mutations occur commonly in advanced prostate cancers prior to endocrine treatment of disease and may contribute to altered androgen responsiveness of the tumors.

Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer

It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.

[Role of androgen receptors in hormone-refractory prostate cancer: molecular basics and experimental therapy approaches].

The first in vivo studies showed that the AR is still expressed or is even overexpressed in hormone-refractory PCA, and these findings should lead to the development of new therapeutic strategies.

Analysis of genetic changes underlying local recurrence of prostate carcinoma during androgen deprivation therapy.

The findings suggest that hormone-refractory prostate cancers are genetically very complex and show intratumor genetic heterogeneity.

Androgen receptor involvement in the progression of prostate cancer.

Genetic diagnosis and/or molecular-targeted therapy via AR pathways can be developed for hormone-refractory states and several co-factors between ARs and the transcriptional complex have been cloned and reports indicate that steroid receptor co-activator 1 is correlated with the hormone- Refractory progression of prostate cancer.

The androgen receptor: genetic considerations in the development and treatment of prostate cancer

Clinically, these mutations are important because they may lead to the growth of androgen-independent tumors and progression to a refractory state, and further characterization of AR mutations will lead to a more thorough understanding of their role in the development of prostate carcinomas.

Molecular analysis of the androgen receptor in ten prostate cancer specimens obtained before and after androgen ablation.

It is concluded that in specific circumstances, AA treatments can select variant forms of the AR in the prostate of patients affected by prostate cancer.

Amplification and protein expression of androgen receptor gene in prostate cancer cells: Fluorescence in situ hybridization analysis.

An influential role of AR in tumor growth and progression even after the deprivation of androgen is demonstrated, as well as showing the potential contribution of AR amplification to AR activation even in the relative absence of androgens.



Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers.

Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone-binding domain of the androgen receptor (AR) gene, suggesting that this frequently observed AR mutation may contribute to the treatment refractory disease.

Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone.

Data demonstrate that the exchange of a single valine into methionine at position 715 in the AR promoters trans-activation not only by testicular but also by adrenal androgens and progesterone may have significance in the process controlling the progression of prostatic carcinoma.

Molecular biology of prostate cancer.

Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers, and may be critical to the acquisition of metastatic potential of aggressive prostate cancers.

Growth factors and oncogenes in prostate cancer.

In vivo animal models have shown that relevant growth factors and oncogenes can induce both premalignant and malignant changes in prostate tissue, and additional experimental and clinical studies are needed to present a clearer molecular profile of this important malignancy.

Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization.

The CGH results indicate that losses of several chromosomal regions are common genetic changes in primary tumors, suggesting that deletional inactivation of putative tumor suppressor genes in these chromosomal sites is likely to underlie development of prostate cancer.

Science behind total androgen blockade: from gene to combination therapy.

Combination therapy permits, for the first time, to prolong life in advanced prostate cancer and offers the possibility of a major improvement in the efficacy of a curative therapy, namely, radical prostatectomy in early stage disease.

Microsatellite mutation (CAG24-->18) in the androgen receptor gene in human prostate cancer.

Direct sequencing revealed that the nontumor tissue contained 24 CAGs, whereas the tumor contained one fragment with 24 C AGs (wild-type) and a second fragment with 18 CAGS (mutant), representing a somatic contraction of the AR CAG repeat (CAG24-->CAG18) in the tumor.

Differential suppression of mammary and prostate cancer metastasis by human chromosomes 17 and 11.

It is demonstrated that when the pter-q23 region of human chromosome 17 is retained by the microcell hybrids, the metastatic ability of both mammary and prostatic cancer cells is suppressed, and that the metastasis suppressor activity encoded by the chromosome 17 pter-$23 region is p53-independent and not due to enhanced expression of NM23 protein.