Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours

Čulig, Zoran; Steiner, Hannes; Bartsch, Georg; Hobisch, Alfred

doi:10.1677/erc.1.00775a

Cited by 90 publications

(54 citation statements)

References 98 publications

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“…3,25,26 The growth-inhibitory effects of endocrine therapies are associated with the status of steroid receptors, such as the androgen receptor (AR) and estrogen receptor (ER). 25,26 The emergence of techniques to clone the orphan nuclear receptors in the 1980s prompted to investigate physiological functions of the orphan nuclear receptors in the targeted organs. 12,13 Among the orphan nuclear receptors, ERRa, b and g, the three closely related members of the ERR family, all have functional links with the activities of the ERs.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of estrogen‐related receptor α (ERRα) is a negative prognostic predictor in human prostate cancer

Fujimura

Takahashi

Urano

et al. 2007

Intl Journal of Cancer

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The nuclear receptor ERRα (estrogen‐related receptor α) is known to modulate the estrogen‐signaling pathway, but the biological significance of ERRα in the prostate remains unclear. We investigated the expression of ERRα in human prostate tissues and cancer cell lines to evaluate the potential roles of the receptor in prostate cancer (PC). Western blot analysis of ERRα was performed in three cell lines of human PC (LNCaP, DU145 and PC‐3). The expressions of ERRα in cancerous lesions (n = 106) and benign foci (n = 99) of 106 surgically obtained prostate specimens were evaluated by immunohistochemistry. The relationships between the ERRα expression and clinicopathological features were evaluated. Western blot analysis using the polyclonal anti‐ERRα antibody detected a 52 kD band in all three PC cell lines. Positive immunostaining of ERRα in the nuclei was found in 73 (69%) cancerous and 47 (47.5%) benign epithelium, whereas the stromal tissues were negative for ERRα. The mean immunoreactivity score (IR score) of the cancerous lesions (3.5 ± 2.6) was significantly higher than that of the benign foci (1.8 ± 2.1) (p < 0.0001). The IR score of the cancerous lesions significantly correlated with the Gleason score (p = 0.0135). Univariate and multivariate hazard analyses revealed significant correlations between elevated ERRα expression and poor cancer‐specific survival (p = 0.0141 and 0.0367, respectively). The enhanced expression of ERRα might play a role in the development of human PC and serve as a significant prognostic factor for the disease. © 2006 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Increased expression of estrogen‐related receptor α (ERRα) is a negative prognostic predictor in human prostate cancer

Fujimura

Takahashi

Urano

et al. 2007

Intl Journal of Cancer

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“…It is probable that binding of H2 relaxin to LGR7 results in the activation of the cAMP/PKA pathway and/or the MAPK pathway. These signaling pathways have been reported to play pivotal roles in CaP progression to AI status (Amorino and Parsons, 2004;Koul et al, 2004;Culig et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7

et al. 2006

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Mutations in p53 occur at a rate of approximately 70% in hormone-refractory prostate cancer (CaP), suggesting that p53 mutations facilitate the progression of CaP to androgen-independent (AI) growth. We have previously reported that transfection of p53 gain of function mutant alleles into LNCaP, an androgen-sensitive cell line, allows for AI growth of LNCaP in vitro. We herein confirm the in vivo relevance of those findings by demonstrating that the R273H p53 mutation (p53 R273H ) facilitates AI growth in castrated nude mice. In addition, we demonstrate that H2 relaxin is responsible for facilitating p53 R273H -mediated AI CaP. H2 relaxin is overexpressed in the LNCaP-R273H subline. Downregulation of H2 relaxin expression results in significant inhibition of AI growth, whereas addition of recombinant human H2 relaxin to parental LNCaP promotes AI growth. Inhibition of AI growth was also achieved by blocking expression of LGR7, the cognate receptor of H2 relaxin. Chromatin immunoprecipitation analysis was used to demonstrate that p53 R273H binds directly to the relaxin promoter, further confirming a role for H2 relaxin signaling in p53 R273H -mediated AI CaP. Lastly, we used a reporter gene assay to demonstrate that H2 relaxin can induce the expression of prostate-specific antigen via an androgen receptor-mediated pathway.

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“…The mechanism of AI proliferation of PC is poorly understood, and many hypotheses have been proposed, such as androgen receptor (AR) amplification (4), AR mutation (3), aberrant activation of AR (5), or increased AR sensitivity to low levels of androgen in the prostate (6,7). In addition, many studies have shown that neuroendocrine (NE) differentiation (NED) may contribute to AI growth of PC (8 -10).…”

Section: Prostate Cancer (Pc)mentioning

confidence: 99%

Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer

Huang

2007

Journal of Biological Chemistry

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Hormonal therapy of prostate cancer, by inhibiting androgen production and/or androgen function, is the treatment of choice for advanced prostate cancer. Although most patients respond initially, the effect is only temporary, and the tumor cells will resume proliferation in an androgen-deprived environment. The mechanism for androgen-independent proliferation of cancer cells is unclear. Hormonal therapy induces neuroendocrine differentiation of prostate cancer cells, which is hypothesized to contribute to tumor recurrence by a paracrine mechanism. We studied signal transduction pathways of neuroendocrine differentiation in LNCaP cells after androgen withdrawal, and we showed that both the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway and ERK are activated, but only the former is required for neuroendocrine differentiation. A constitutively active AKT promotes neuroendocrine differentiation and a dominant negative AKT inhibits it. Activation of AKT by IGF-1 leads to neuroendocrine differentiation, and neuroendocrine differentiation induced by epinephrine requires AKT activation. We also show that the AKT pathway is likely responsible for neuroendocrine differentiation in DU145, an androgen-independent prostate cancer cell line. Therefore, our study demonstrated a novel function of the AKT pathway in prostate cancer progression and identified potential targets that may be explored for the treatment of androgen-independent cancer.

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Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours

Cited by 90 publications

References 98 publications

Increased expression of estrogen‐related receptor α (ERRα) is a negative prognostic predictor in human prostate cancer

Increased expression of estrogen‐related receptor α (ERRα) is a negative prognostic predictor in human prostate cancer

The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7

Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer

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