Two Mutations Identified in the Androgen Receptor of the New Human Prostate Cancer Cell Line Mda Pca 2a

Zhao, Xianda; Boyle, Bryan; Krishnan, Aruna V.; Navone, Nora M.; Peehl, Donna M.; Feldman, David

doi:10.1016/s0022-5347(05)68158-x

Cited by 99 publications

(64 citation statements)

References 11 publications

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“…31,37 The two prostate cancer cell lines, LNCaP and MDA PCa 2a, obtained from patients with metastatic disease contain mutated ARs that are activated by hydroxyflutamide but not by bicalutamide. 38,39 There is a consensus that frequency of AR point mutations in prostate cancer increases with progression toward resistance to therapy. 40,41 For these reasons, it is important to study the mechanisms by which hydroxyflutamide acquires agonistic properties in human prostate cancer.…”

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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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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“…This mutation is frequently detected in patients with metastatic PCa who received combined androgen blockade with flutamide as an anti-androgen (16 -18). Since then, additional mutations have been described, including the V715M mutant AR which binds adrenal androgens with higher affinity than wild-type AR (19), the C685Y mutant which binds oestrogens, progestagens and anti-androgens (20), and the L701H and L701H/T877A mutants which are responsive to glucocorticoids (21,22). In advanced PCa, the presence of tumour clones with such AR mutations should be taken into consideration as hormonal therapies may ultimately exert a positive selection of these tumour cells.…”

Section: Introductionmentioning

confidence: 99%

A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer

Céraline

Erdmann²,

Erbs³

et al. 2003

European Journal of Endocrinology

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Objective: Mutations in the ligand-binding domain of the human androgen receptor (AR) figure among the ways used by prostate adenocarcinoma (PCa) cells to escape androgen dependence. These mutations may broaden the specificity and/or affinity of the AR to other hormones, resulting in inappropriate receptor activation and thus affecting the PCa response to physiological stimuli and hormonal therapies. Design: In order to clarify the impact of these mutations on disease progression and treatment, we have developed a yeast-based functional assay that allows the detection of mutant ARs and the analysis of their transactivation capacities in response to different ligands. Methods: AR cDNA was directly cloned into an expression vector in a yeast strain that carries a reporter gene (ADE2 ) linked to an androgen-dependent promoter. The expression of the ADE2 gene and consequently the yeast cell growth in a selective medium depleted in adenine depends on the specificity of the AR for the ligand added to the medium. Results: By analysing the transactivation capacities of different AR molecules in response to a broad range of steroid and non-steroid ligands, we have demonstrated that this assay can discriminate among wild-type AR, T877A, C685Y and L701H mutant ARs and that at least 1% of mutant ARs could be detected when mutant and wild-type ARs were mixed at the cDNA level. Conclusions:The data presented here show that this simple AR assay is convenient for the routine detection of mutant ARs in PCa and is also suitable to evaluate the antagonist activities of anti-androgen molecules.

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“…4,9 Much of our understanding of AR function is derived from the study of somatic missense mutations in the AR gene in patients with androgen insensitivity syndrome (inactivating mutations) or in primary, recurrent and metastatic prostate tumors and cell lines. [10][11][12] AR variants identified in clinical prostate tumors typically exhibit promiscuous activation by nonandrogenic ligands and/or enhanced transactivation capacity due to altered interactions with coregulators. 13 The prototypical example of AR promiscuity is AR-T877A (T857A in mice), a variant expressed in the LNCaP prostate cancer cell line that is activated by estrogen, progesterone and the AR antagonist, hydroxyflutamide, in addition to androgens.…”

mentioning

confidence: 99%

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

Thompson

Day

Bianco‐Miotto

et al. 2012

Intl Journal of Cancer

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Mutations in the androgen receptor (AR) have been detected in experimental and clinical prostate tumors. Mice with enforced prostate-specific expression of one such receptor variant, AR-E231G, invariably develop prostatic intraepithelial neoplasia by 12 weeks and metastatic prostate cancer by 52 weeks. The aim of this study was to identify genes with altered expression in the prostates of AR-E231G mice at an early stage of disease that may act as drivers of AR-mediated tumorigenesis. The gene expression profile of AR-E231G prostate tissue from 12-week-old mice was compared to an equivalent profile from mice expressing the AR-T857A receptor variant (analogous to the AR-T877A variant in LNCaP cells), which do not develop prostate tumors. One hundred and thirty-two genes were differentially expressed in AR-E231G prostates. Classification of these genes revealed enrichment for cellular pathways known to be involved in prostate cancer, including cell cycle and lipid metabolism. Suppression of two genes upregulated in the AR-E231G model, ADM and CITED1, increased cell death and reduced proliferation of human prostate cancer cells. Many genes differentially expressed in AR-E231G prostates are also deregulated in human tumors. Three of these genes, ID4, NR2F1 and PTGDS, which were expressed at consistently lower levels in clinical prostate cancer compared to nonmalignant tissues, formed a signature that predicted biochemical relapse (hazard ratio 2.2, p 5 0.038). We believe that our findings support the value of this novel mouse model of prostate cancer to identify candidate therapeutic targets and/or biomarkers of human disease.

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Two Mutations Identified in the Androgen Receptor of the New Human Prostate Cancer Cell Line Mda Pca 2a

Cited by 99 publications

References 11 publications

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

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

A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

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