Prostate Cancer Prevention: Agent Development Strategies

Parnes, Howard L.; House, Margaret G.; Tangrea, Joseph A.

doi:10.1007/978-3-642-45195-9_15

Cited by 5 publications

(3 citation statements)

References 36 publications

(24 reference statements)

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“…As the most common malignancy in males worldwide, an increasing number of studies have focused on improving the prevention and treatment of PCa (22). Although various advanced therapeutic strategies exist, the outcomes for patients with PCa are far from ideal (23).…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of bromodomain‑containing protein 7 and its association with tumor progression in prostate cancer

et al. 2018

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Prostate cancer (PCa) is a common malignancy in males. The current study assessed the clinical significance of bromodomain-containing protein 7 (BRD7) and its association with PCa tumor progression. Serum and tissue expression levels of BRD7 were analyzed by reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic value of BRD7. Kaplan-Meier survival analysis and Cox regression analysis were performed to assess the prognostic performance of BRD7. The association of BRD7 with cell behavior was investigated by transfection with a pcDNA3.1-BRD7 vector. The results revealed that serum and tissue BRD7 expression levels were significantly decreased in PCa samples compared with normal controls (P<0.001). BRD7 expression was significantly associated with the pathological stage (P=0.037), lymph node metastasis (P=0.009) and TNM stage (P=0.010). An area under the ROC curve of 0.864 was obtained, with a sensitivity and specificity of 77.0 and 83.3%, respectively. Low BRD7 expression was significantly associated with a shorter survival time in both overall survival analysis (P=0.003) and cancer-specific survival analysis (P=0.029). Furthermore, BRD7 appeared to serve as an independent prognostic factor for PCa. The proliferation, migration and invasion of PCa cells were suppressed by BRD7 overexpression. In summary, downregulation of BRD7 in PCa may be involved in tumor progression and serve as an effective diagnostic and prognostic biomarker.

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Section: Discussionmentioning

confidence: 99%

Clinical significance of bromodomain‑containing protein 7 and its association with tumor progression in prostate cancer

et al. 2018

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“…Prostate cancer remains the most common male malignancy and the second most common form of male cancer death [ 1 - 3 ]. The common characteristic of the disease through its clinical progression is androgen receptor activation, which is initially accomplished by systemic androgens.…”

Section: Introductionmentioning

confidence: 99%

The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes

et al. 2013

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Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that coordinately promote both cholesterol efflux and androgen catabolism. Thus, loss of TERE1 during tumor progression reduces K-2 levels resulting in reduced transcription of SXR target genes. We propose that TERE1 controls the CPRC phenotype by regulating the endogenous levels of Vitamin K-2 and hence the transcriptional control of a suite of steroidogenic genes via the SXR receptor. These data implicate the TERE1 protein as a previously unrecognized link affecting cholesterol and androgen accumulation that could govern acquisition of the CRPC phenotype.

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“…The prostate is a major exocrine gland in males, which is involved in sexual developments (1). The prostate organ grows gradually during puberty by stimuli of male hormone androgen in the body (2).…”

Section: Introductionmentioning

confidence: 99%

The estrogen receptor signaling pathway activated by phthalates is linked with transforming growth factor-β in the progression of LNCaP prostate cancer models

Lee

Hwang

Choi

2014

International Journal of Oncology

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The distinct roles of estrogen receptors (ERs) related with androgen receptors (ARs) have been proposed in prostate cancer, while the involvement of transforming growth factor-β (TGF-β) has been reported in the progression of prostate cancer. In this study, we examined whether the TGF-β signaling pathway is associated with ER signaling in LNCaP prostate cancer cells, which express ERα, ERβ and ARs. We determined whether the exposure to phthalates may induce prostate cancer progression by affecting molecular crosstalk between ER and TGF-β signaling pathways. Cell viability was measured in LNCaP cells by MTT assay following treatment with di-n-buthyl phthalate (DBP). RT-PCR and immunoblot assay were performed to examine the expression levels of cell cycle-related genes and the TGF-β signaling cascade. A mouse xenograft model of prostate cancer was generated, and immunohistochemical and BrdU assay were carried out to determine the effect of DBP in this mouse model. DBP, a type of phthalate, was shown to promote LNCaP cell proliferation by upregulating the gene expression of c-myc and cyclin D1 and by downregulating the expression of p21. DBP significantly reduced the protein expression of p-smad similarly to E2. These regulations caused by DBP were reversed by ICI 182,780, an ER antagonist, indicating that DBP may affect crosstalk between TGF-β and ER signals. In an in vivo mouse model, tumor volume of mice exposed to DBP was increased. Number of cells in S phase of cell cycle was increased by DBP, while expression of p21 protein was reduced in the tissues of DBP-treated mice. These results indicate that DBP may induce the growth of LNCaP prostate cancer by acting on the crosstalk between TGF-β and ER signaling pathways.

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Prostate Cancer Prevention: Agent Development Strategies

Cited by 5 publications

References 36 publications

Clinical significance of bromodomain‑containing protein 7 and its association with tumor progression in prostate cancer

Clinical significance of bromodomain‑containing protein 7 and its association with tumor progression in prostate cancer

The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes

The estrogen receptor signaling pathway activated by phthalates is linked with transforming growth factor-β in the progression of LNCaP prostate cancer models

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