Expression, structure, and function of androgen receptor in advanced prostatic carcinoma

Čulig, Zoran; Hobisch, Alfred; Hittmair, A; Peterziel, Heike; Cato, Andrew C. B.; Bartsch, Georg; Klocker, Helmut

doi:10.1002/(sici)1097-0045(19980401)35:1<63::aid-pros9>3.0.co;2-i

Cited by 119 publications

(79 citation statements)

References 61 publications

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“…Most androgenindependent prostate cancer cells express androgen receptors, which suggests that in these patients, the androgen receptor signaling pathways may be activated even in the absence of androgens. 35 Peptide growth factors and their receptors have been implicated in prostate cancer by virtue of the fact that they modulate androgen receptor signaling and determine progression to a hormone-refractory state. Experimental studies have demonstrated functional crosstalk between growth factors and growth factor receptors of the EGFR family and the androgen receptor-activated pathway.…”

Section: Discussionmentioning

confidence: 99%

Expression of biomarkers modulating prostate cancer progression: implications in the treatment of the disease

Lorenzo

Placido

Autorino

et al. 2005

Prostate Cancer Prostatic Dis

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Objectives: To determine whether COX-2, bcl-2 and neoangiogenesis are related to human prostate cancer relapse after definitive surgical treatment and progression toward androgen independence and to evaluate the association between the patterns of these tumoral biomarkers and other standard clinico-pathological parameters (such as Gleason score, PSA, TNM stage). Materials and Methods: We retrospectively analyzed the records on 126 prostate cancer samples from patients treated at our University Hospital from 1995 to 2002. The 72 patients with clinically localized disease (group 1) had undergone radical prostatectomy. Another 54 patients (group 2) had metastatic androgen-independent disease. Archived material relating to the subjects was then immunostained for bcl-2, COX-2 and CD-31, using an anti-bcl-2 monoclonal primary antibody, an anti-COX-2 polyclonal rabbit antibody and an anti-CD-31 monoclonal mouse antibody to evaluate neoangiogenesis (MVD, microvessel density). Results: We found that bcl-2, COX-2 and MVD expression increased from group 1 to group 2. The intergroup difference was significant only for high MVD (Po0.05). On the other hand, high MVD, high bcl-2 and high COX-2 expression was correlated with a higher PSA level (Po0.01), whereas only a high MVD was also related with Gleason score (Po0.05). We used univariate analysis to evaluate the prognostic impact of biologic and clinico-pathologic parameters on the diseasefree-survival of 72 patients treated by radical prostatectomy. A total of 30 patients (41.6%) experienced biochemical relapse; bcl-2, COX-2 and MVD significantly correlated with disease relapse in these patients. In fact, we observed disease relapse in 24/45 (53%) with high bcl-2 expression, in 15/21 (71%) with a high MVD count and finally, in 30/58 (52%) with high COX-2 expression. Finally, PSA value and Gleason score were the only two biologic markers significantly associated to disease relapse in a multivariate analysis. Conclusions: Our results strongly support a role for bcl-2, COX-2 and angiogenesis in the development and progression of prostate cancer. Of course, we are aware of the small sample size considered in our study. Further investigations would better clarify the prognostic and therapeutic implications of these findings.

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Section: Discussionmentioning

confidence: 99%

Expression of biomarkers modulating prostate cancer progression: implications in the treatment of the disease

Lorenzo

Placido

Autorino

et al. 2005

Prostate Cancer Prostatic Dis

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“…b-Catenin has recently been shown to enhance AR target gene expression in LNCaP and AR-transfected TSU cells, reportedly through its involvement in AR complexes (Truica et al, 2000). Aberrant AR co-activation, along with AR gene ampli®cation and mutation, is theorized as an important event leading to conversion of androgendependent disease to the lethal, androgen-independent form (Culig et al, 1998). Since this phenomenon potentially constitutes a major role for b-catenin in CaP, we wished to examine this interaction further.…”

Section: Ar Signaling Enhancement By B-cateninmentioning

confidence: 99%

“…Although our ability to detect early stage tumors has increased, predictive diagnosis and e ective tumor therapy remain limited, thereby incurring greater morbidity rates. Advanced CaP brought to remission with hormonal ablative therapy often relapses, leading to androgen-independent tumors for which only experimental treatments exist (Culig et al, 1998). Urgently needed is a better understanding of CaP progression at the molecular level in order to reveal new targets for novel therapy design.…”

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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“…This effect is however, transient (Newling et al, 1997) with the majority of patients developing androgen resistance (Newling et al, 1997). The mechanisms involved with the development of resistance are poorly understood, but AR mutations (Avila et al, 2001), AR amplification (Visakorpi et al, 1995), increased AR expression (Gregory et al, 1998) and activation of the AR by interaction with other signalling pathways have been implicated (Culig et al, 1998).…”

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confidence: 99%

Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer

et al. 2003

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This study examined androgen receptor (AR) gene amplification and protein expression in 102 matched paired hormone sensitive and resistant tumours from 51 patients. AR gene amplification and X chromosome copy number were assessed by fluorescent in situ hybridisation, and protein expression was assessed by immunohistochemistry. All tumours were stained for PSA protein expression. Significantly more tumours exhibited AR amplification following the development of hormone resistance (20%, 10 out of 49) compared to matched hormone-sensitive tumours from the same patient (2%, one out of 48) (P ¼ 0.0085). The level of AR expression was significantly higher in hormone-resistant tumours compared to matched hormone-sensitive tumours from the same patient (130, interquartile range, 55 -167 vs 94.5 interquartile range, 55 -120, P ¼ 0.019). AR expression levels in hormone-resistant tumours with and without AR amplification were not significantly different. However, an increase in AR expression was seen with the development of AR amplification in paired tumours. The rate of AR gene amplification and/or an increase in AR protein expression during androgen resistant is too low to wholly explain the development of androgen resistance. Alternative mechanisms for modulating the function of the AR, or other signalling pathways, must be considered as key factors in the development of hormoneresistant prostate.

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Expression, structure, and function of androgen receptor in advanced prostatic carcinoma

Cited by 119 publications

References 61 publications

Expression of biomarkers modulating prostate cancer progression: implications in the treatment of the disease

Expression of biomarkers modulating prostate cancer progression: implications in the treatment of the disease

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

Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer

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