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

Cude, Kelly J.; Dixon, Shannon C.; Guo, Yunfei; Lisella, Jordan; Figg, William D.

doi:10.1007/s001090050372

Cited by 36 publications

(20 citation statements)

References 60 publications

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“…AR is also involved in the proliferation of some androgen-dependent tumors, the most well known of which is prostatic cancer (10,11). Many synthetic compounds have been made which either stimulate or antagonize the transactivation functions of nuclear receptors.…”

Section: Androgen Receptor (Ar)mentioning

confidence: 99%

The Subnuclear Three-dimensional Image Analysis of Androgen Receptor Fused to Green Fluorescence Protein

Tomura

Goto²,

Morinaga³

et al. 2001

Journal of Biological Chemistry

130

128

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To establish the novel approach in order to distinguish the transcriptionally active androgen receptor (AR) from the transcriptionally inactive AR, we performed the three-dimensional construction of confocal microscopic images of intranuclear AR. This method clearly distinguished the subnuclear localization of transcriptionally active AR tagged with green fluorescent protein (AR-GFP) from the transcriptionally inactive AR-GFP. Transcriptionally active AR-GFP mainly produced 250 -400 fluorescence foci in the boundary region between euchromatin and heterochromatin. Although the AR-GFP bound to such antiandrogens as hydroxyflutamide or bicalutamide translocated to the nucleus, they homogeneously spread throughout the nucleus without producing any fluorescence foci. Antiandrogenic environmental disrupting chemicals, such as 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene, vinclozolin, or nitrofen, also disrupted the intranuclear fluorescence foci. A point mutation (T877A) resulted in the loss of ligand specificity in AR-GFP. Even in this mutant receptor, agonists, such as dihydrotestosterone, hydroxyflutamide, or progesterone, produced the fluorescence foci in the nucleus, whereas the transcriptionally inactive mutant binding bicalutamide was observed to be spread homogeneously in the nucleus. Taken together, our findings suggest that, after nuclear translocation, AR is possibly located in the specific region in the nucleus while demonstrating clustering tightly depending on the agonist-induced transactivation competence.

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Section: Androgen Receptor (Ar)mentioning

confidence: 99%

The Subnuclear Three-dimensional Image Analysis of Androgen Receptor Fused to Green Fluorescence Protein

Tomura

Goto²,

Morinaga³

et al. 2001

Journal of Biological Chemistry

130

128

View full text Add to dashboard Cite

show abstract

“…Central to processes of prostate growth, di erentiation, and tumorigenesis is androgen receptor (AR) signaling (Culig et al, 1998;Cude et al, 1999). Current models place inactive AR in the cytosol where, upon binding its ligand dihydrotestosterone, it undergoes a conformational change accompanied by nuclear translocation.…”

Section: Introductionmentioning

confidence: 99%

“…In a homodimeric fashion, ligand-bound AR binds speci®c DNA elements in target gene promoter and enhancer regions, upregulating expression via recruitment of other transcription factors (e.g. p160 proteins) to its amino terminus (Cude et al, 1999). Target genes include those related to both cell cycle progression (CDK2) and secretory function (kallikrein expression).…”

Section: Introductionmentioning

confidence: 99%

“…Several mechanisms, all of which are founded on resumption of AR signaling, have been proposed to explain progression to androgen-independence. Missense mutations in the ligand binding domain can impart promiscuous behavior to AR, often resulting in its nuclear induction by female steroids and certain anti-androgens used for ablative therapy (Cude et al, 1999). Such mutations, and increased AR levels resulting from gene ampli®cation (Linja et al, 2001), may restore androgen sensitivity to metastatic prostate tumor cells in an otherwise androgen-scarce milieu.…”

Section: Introductionmentioning

confidence: 99%

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In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis

Chesire¹,

Ewing²,

et al. 2002

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Understanding the molecular etiology of prostate cancer (CaP) progression is paramount for broadening current diagnostic and therapeutic modalities. Current interest in the role of wnt pathway signaling in prostate tumorigenesis was generated with the ®nding of b-catenin mutation and corresponding nuclear localization in primary lesions. The recent ®nding of b-catenin-induced enhancement of androgen receptor (AR) function potentially ties b-catenin to key regulatory steps of prostate cell growth, di erentiation, and transformation. By immunohistological analysis of metastatic tumors, we detected nuclear bcatenin in 20% of lethal CaP cases, suggesting a more common role for b-catenin in advanced disease than would be predicted by its mutation rate. Interestingly, bcatenin nuclear localization was found to occur concomitantly with androgen-induced regrowth of normal rat prostate. These in vivo observations likely implicate b-catenin involvement in both normal and neoplastic prostate physiology, thus prompting our interest in further characterizing modes of b-catenin signaling in prostate cells. Extending our previous ®ndings, we demonstrate that transient b-catenin over-expression stimulates T cell factor (TCF) signaling in most CaP cell lines. Further, this activity is not subject to crossregulation by phosphoinositide-3-kinase (PI3-K)/Akt signaling, a stimulatory pathway often upregulated in CaP upon PTEN inactivation. Consistent with a previous report, we observed that transient b-catenin overexpression enhances AR-mediated transcription o two natural target gene promoters. However, we were unable to recapitulate b-catenin-induced stimulation of ectopically expressed AR in AR-negative cells, suggesting that other AR-associated factors are required for this activity. Although LNCaP cells are capable of this mode of AR co-stimulation, stable expression of mutant b-catenin did not alter their proliferative response to androgen. In total, our characterization of b-catenin signaling in CaP reveals the complex nature of its activity in prostate tissue, indicating that b-catenin potentially contributes to multiple stimulatory inputs required for disease progression.

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“…Firstly, tumor cells in EMPD show differentiation to apocrine sweat glands (Guarner et al, 1989), which normally express androgen receptor (Blauer et al, 1991;Choudhry et al, 1992;Kurata et al, 1990). Secondly, the androgen receptor is a liganddependent transcriptional factor that regulates tissuespecific genes involved in cellular proliferation and differentiation (Cude et al, 1999). Thirdly, the action of androgens and other hormones via the androgen receptor is well documented in the development and growth of carcinomas derived from other exocrine glands such as the prostate and the breast (Hackenberg and Schulz, 1996;Kallioniemi and Visakorpi, 1996).…”

mentioning

confidence: 99%

Expression of Structurally Unaltered Androgen Receptor in Extramammary Paget's Disease

Fujimoto

Takata

Hatta

et al. 2000

Laboratory Investigation

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SUMMARY: Extramammary Paget's disease (EMPD) is an uncommon neoplasm of the skin that shows differentiation to an apocrine sweat gland. Although we previously showed that erbB-2 overexpression may play a part in the progression of EMPD, molecular genetic defects underlying the development of EMPD are poorly understood. In the study described here, we examined androgen receptor expression and gene alterations in 30 cases of EMPD without internal malignancy. Immunohistochemistry revealed that 24 of 30 (80%) cases of EMPD variably expressed nuclear androgen receptor. Semi-quantitation of receptor content by scoring immunostained sections showed no difference between in situ (n ϭ 17) and invasive (n ϭ 13) EMPD tumors. Androgen receptor expression was also observed in four of six lymph node metastases. In these lymph nodes, expression of androgen receptor mRNA was confirmed by reverse transcriptase-polymerase chain reaction. Direct sequencing of exon 2 through exon 8, which encodes DNA-and hormone-binding domains of the androgen receptor gene, revealed no mutation in any of the 10 advanced stage tumors. Neither amplification nor deletion of the androgen receptor gene locus was detected by dual color fluorescence in situ hybridization analysis in 14 tumors. The present findings showing frequent expression of structurally unaltered androgen receptor in an advanced stage of EMPD may provide a rational basis for hormone therapy, which is widely used in the treatment of metastatic prostate cancer and androgen receptor-positive breast cancer recurrence. (Lab Invest 2000, 80:1465-1471.E xtramammary Paget's disease (EMPD) is an uncommon neoplasm of apocrine gland-bearing skin, that most commonly involves the vulvar, perianal, perineal, scrotal, and penile regions (Heymann, 1993). Although it is rarely associated with underlying adenocarcinoma, it mostly begins as an intraepidermal adenocarcinoma that can invade the dermis and may metastasize via the lymphatic system (Feuer et al, 1990;Hart and Millman, 1977;Jones et al, 1979;Murata et al, 1999). The histogenesis of EMPD has long been disputed. Emerging information, however, supports the concepts that Paget's cells in EMPD are of glandular origin, usually showing apocrine differentiation and that the disease may arise from a pluripotential epidermal precursor (Guarner et al, 1989;Mazoujian et al, 1984;Roth et al, 1977).The molecular genetic defects underlying EMPD are poorly understood. We previously showed that erbB-2 overexpression by either gene amplification or transcriptional activation may play a part in the progression of EMPD (Takata et al, 1999). However, other molecular genetic defects, including p53 mutations, allelic loss of several selected chromosome arms as well as abnormal activation of the ␤-catenin gene, which are commonly seen in other epithelial malignancies, were not detected in EMPD (Takata et al, 1999;Takata et al, 1997). To explore further the molecular pathogenesis of EMPD, we aimed at examining androgen receptor expression in Paget's cells of EMPD f...

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

Cited by 36 publications

References 60 publications

The Subnuclear Three-dimensional Image Analysis of Androgen Receptor Fused to Green Fluorescence Protein

The Subnuclear Three-dimensional Image Analysis of Androgen Receptor Fused to Green Fluorescence Protein

In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis

Expression of Structurally Unaltered Androgen Receptor in Extramammary Paget's Disease

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