Androgen Receptor Gene Amplification and Protein Expression in Recurrent Prostate Cancer

Ford, O. Harris; Gregory, Christopher; Kim, Desok; Smitherman, Andrew B.; Mohler, James L.

doi:10.1097/01.ju.0000091873.09677.f4

Cited by 133 publications

(99 citation statements)

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“…Constitutively high AR expression has been found in hormone refractory tumors, but lower expression of the AR was noted during regression of hormonally treated PCa. 21,22,[27][28][29][30] AR amplification may contribute to its own activation in a relative absence of androgens; moreover, AR appears to undergo structural and functional alterations during PCa progression. We have previously observed that bicalutamide is able to inhibit significantly and dose-dependently the proliferation of established AR-positive human PCa cell lines and of primary cultures of PCa cells obtained directly from clinical samples.…”

Section: Discussionmentioning

confidence: 99%

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Festuccia

Gravina

Angelucci

et al. 2005

Intl Journal of Cancer

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Progression from an androgen-dependent to an androgen-independent state often occurs in patients with prostate cancer (PCa) who undergo hormonal therapy. We have investigated whether inhibition of the epidermal growth factor receptor (EGFR) signaling pathway affects the antitumor effect of a nonsteroidal antiandrogen. Gefitinib (Iressa), an EGFR tyrosine kinase inhibitor, and bicalutamide (Casodex), a nonsteroidal antiandrogen [androgen receptor (AR) antagonist], were administered alone and in combination to AR-positive human PCa cell lines. FACS analysis showed lower EGFR expression levels on AR-positive cells (LNCaP, CWR22, CWR22R 2152 and AR-transfected DU145 cell lines) compared with AR-negative cells (DU145, PC3 and TSUPr1). Moreover, in AR-transfected DU145 cells, chronic treatment with bicalutamide increased EGFR expression to levels similar to androgen-independent DU145 cells. All AR-positive PCa cell lines were sensitive to gefitinib (IC 50 = 0.1-0.6 mM), whereas higher concentrations of bicalutamide were needed to reduce AR-positive PCa cell line proliferation (IC 50 = 0.8-2.0 mM). Low doses of gefitinib increased the antitumor effects of bicalutamide by strongly reducing the IC 50 of bicalutamide (approximately 10-fold). Similarly, bicalutamide increased the antiproliferative effects of gefitinib by reducing the IC 50 of gefitinib (approximately 5-fold). Taken together, our data suggest that in androgen-dependent cell lines, addition of gefitinib in combination with bicalutamide results in concurrent dual inhibition of AR and EGFR/HER2 pathways. This causes a significant delay in the onset of EGFRdriven androgen independence. ' 2005 Wiley-Liss, Inc. Key words: prostate cancer; hormonal therapy; EGFR; androgenindependent tumorsIn industrialized countries, prostate cancer (PCa) is the most frequently occurring malignancy in men, representing the second highest cause of cancer-related death. PCa usually begins as an androgen-sensitive, androgen-dependent (AD), nonmetastatic cancer, which without intervention may follow a gradual transition into a highly metastatic and then androgen-insensitive (AI) variety. The androgen receptor (AR) is a nuclear receptor that cooperates with multiple proteins to exert its biologic function. Upon binding to the ligand testosterone/5 -dihydrotestosterone (DHT), the AR can bind to the androgen response element (ARE) on the 5 0 promoter of target genes, resulting in the modulation of cell growth. Until relatively recent times, endocrine response pathways in PCa were described solely in terms of the intracellular pathways used by the androgens and the subsequent destructive effects exerted on AR signaling by antihormonal treatments. 1 It is widely accepted that androgens promote tumor growth by binding to ARs and acting as nuclear transcription factors that regulate the expression of genes involved in cell proliferation and survival mechanisms. In contrast, hormonal therapies promote tumor regression either by reducing the amount of androgens available to the tumor cells or...

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Section: Discussionmentioning

confidence: 99%

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Festuccia

Gravina

Angelucci

et al. 2005

Intl Journal of Cancer

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“…With regards to the situation in hormone refractory PCa cells found in specimens obtained from patients, there is evidence that these cells have upregulated hAR mRNA (Gil-Diez de Medina et al, 1998;Latil et al, 2001) as well as hAR protein (Ford et al, 2003). Similar findings are also reported for human PCa cell xenografts (Chen et al, 2004a) and cultured PCa cells that are chronically deprived of androgen (Shi et al, 2004).…”

Section: Discussionmentioning

confidence: 73%

“…This conundrum has led to extensive research to determine mechanisms through which androgen signaling might be maintained in PCa cells in hormone-treated patients. Various studies reveal that there are likely multiple pathways leading to increased androgen signaling in a low androgen environment involving mechanisms as diverse as hAR gene amplification (Ford et al, 2003), mutations that alter the ligand specificity of the hAR (Tilley et al, 1996) or by association of the hAR protein with coactivators that cooperate to increase transcriptional activity of hAR (Rahman et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells

et al. 2006

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“…19 The expression of AR protein in tumors with amplification has been reported to be high. 18,25 However, it was also seen that although protein expression was increased in 80% of HR tumors with amplification, tumors without amplification also showed an increase in protein expression 25 as seen in the case of mRNA expression. Amplification has also been correlated to PSA expression and survival.…”

Section: Amplification Of the Armentioning

confidence: 88%

“…16,17 Amplification of the AR gene was seen in approximately 20-30% of all HR tumors. [18][19][20][21][22][23] In addition, there was heterogeneity in the amplification seen within tumors. 22 These studies indicated that since amplification is seen in refractory tumors, only the clones having the amplifications would be selected for further growth in a low-androgen environment, and would accumulate the chromosomal changes with time to establish aggressive disease.…”

Section: Amplification Of the Armentioning

confidence: 99%

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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Androgen Receptor Gene Amplification and Protein Expression in Recurrent Prostate Cancer

Abstract: AR amplification in recurrent prostate cancer results in higher levels of AR protein expression but does not affect survival.

Cited by 133 publications

References 10 publications

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells

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

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