Prostate tumorigenesis induced by PTEN deletion involves estrogen receptor β repression.

The role of ERβ in prostate cancer is unclear, although loss of ERβ is associated with aggressive disease. Given that mice deficient in ERβ do not develop prostate cancer, we hypothesized that ERβ loss occurs as a consequence of tumorigenesis caused by other oncogenic mechanisms and that its loss is necessary for tumorigenesis. In support of this hypothesis, we found that ERβ is targeted for repression in prostate cancer caused by PTEN deletion and that loss of ERβ is important for tumor formation.

β1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1.

This study was carried out to dissect the mechanism by which β1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β1 , AIIB2, in a xenograft model.

VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer.

We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1-mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated.

ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading.

High Gleason grade prostate carcinomas are aggressive, poorly differentiated tumors that exhibit diminished estrogen receptor beta (ERbeta) expression. We report that a key function of ERbeta and its specific ligand 5alpha-androstane-3beta,17beta-diol (3beta-adiol) is to maintain an epithelial phenotype and repress mesenchymal characteristics in prostate carcinoma. Stimuli (TGF-beta and hypoxia) that induce an epithelial-mesenchymal transition (EMT) diminish ERbeta expression, and loss of ERbeta is sufficient to promote an EMT.

Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer.

Molecular chaperones of the heat shock protein-90 (Hsp90) family promote cell survival, but the molecular requirements of this pathway in tumor progression are not understood. Here, we show that a mitochondria-localized Hsp90 chaperone, tumor necrosis factor receptor-associated protein-1 (TRAP-1), is abundantly and ubiquitously expressed in human high-grade prostatic intraepithelial neoplasia, Gleason grades 3 through 5 prostatic adenocarcinomas, and metastatic prostate cancer, but largely undetectable in normal prostate or benign prostatic hyperplasia in vivo. Prostate lesions formed in genetic models of the disease, including the transgenic adenocarcinoma of the mouse prostate and mice carrying prostate-specific deletion of the phosphatase tensin homolog tumor suppressor (Pten(pc-/-)), also exhibit high levels of TRAP-1.

Prostate cancer regulatory networks.

Although the timing with which common epithelial malignancies arise and become established remains a matter of debate, it is clear that by the time they are detected these tumors harbor hundreds of deregulated, aberrantly expressed or mutated genes. This enormous complexity poses formidable challenges to identify gene pathways that are drivers of tumorigenesis, potentially suitable for therapeutic intervention. An alternative approach is to consider cancer pathways as interconnected networks, and search for potential nodal proteins capable of connecting multiple signaling networks of tumor maintenance.

Endogenous tumor suppression mediated by PTEN involves survivin gene silencing.

Endogenous tumor suppression provides a barrier against oncogenesis, but the molecular requirements of this process are not well understood. Here, we show that the dual specificity phosphatase PTEN, a gene almost universally altered in human tumors, silences the expression of survivin, an essential regulator of cell division and apoptosis in cancer. This pathway is independent of p53, involves active repression of survivin gene transcription, and is mediated by direct occupancy of the survivin promoter by FOXO1 and FOXO3a factors.

Deletion hotspots in AMACR promoter CpG island are cis-regulatory elements controlling the gene expression in the colon.

Alpha-methylacyl-coenzyme A racemase (AMACR) regulates peroxisomal beta-oxidation of phytol-derived, branched-chain fatty acids from red meat and dairy products -- suspected risk factors for colon carcinoma (CCa). AMACR was first found overexpressed in prostate cancer but not in benign glands and is now an established diagnostic marker for prostate cancer. Aberrant expression of AMACR was recently reported in Cca; however, little is known about how this gene is abnormally activated in cancer.

SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion.

SOX9 is a transcription factor that plays a critical role in the development of multiple tissues. We previously reported that SOX9 in normal human adult prostate was restricted to basal epithelium. SOX9 was also expressed in a subset of prostate cancer (PCa) cells and was increased in relapsed hormone-refractory PCa.

Sex hormones induce direct epithelial and inflammation-mediated oxidative/nitrosative stress that favors prostatic carcinogenesis in the noble rat.

Oxidative and nitrosative stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administration of testosterone plus 17beta-estradiol to Noble rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma.

BMP-5 expression increases during chondrocyte differentiation in vivo and in vitro and promotes proliferation and cartilage matrix synthesis in primary chondrocyte cultures.

Bone morphogenetic proteins (BMPs) play pivotal roles in bone and cartilage growth and repair. Through phenotypes of short-ear (se) mice, which have BMP-5 mutations, a role for BMP-5 in some specific aspects of skeletogenesis and cartilage growth is known. This report examines BMP-5 expression in the growth plate and in differentiating cultures of primary chondrocytes, and the effects of addition of BMP-5 or its inhibition by anti-BMP-5 antibody in chondrocyte cultures.

Functional interaction of the retinoblastoma and Ini1/Snf5 tumor suppressors in cell growth and pituitary tumorigenesis.

The Ini1 subunit of the SWI/SNF chromatin remodeling complex suppresses formation of malignant rhabdoid tumors in humans and mice. Transduction of Ini1 into Ini1-deficient tumor-derived cell lines has indicated that Ini1 arrests cell growth, controls chromosomal ploidy, and suppresses tumorigenesis by regulating components of the retinoblastoma (Rb) signaling pathway. Furthermore, conditional inactivation of Ini1 in mouse fibroblasts alters the expression of various Rb-E2F-regulated genes, indicating that endogenous Ini1 levels may control Rb signaling in cells.

Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis.

Estrogen receptor (ER)-beta is thought to exert anti-proliferative effects in the normal prostate but supports prostate cancer (PCa) cell survival. We previously reported that the receptor's expression declined as PCa developed in the gland but reappeared in lymph node and bone metastases. To investigate whether hypermethylation was the underlying mechanism for these phenomena, we first identified two CpG islands (CGIs) encompassing 41 CpG dinucleotides, located separately in the untranslated exon 0N and the promoter region of ER-beta.

Estrogen receptor-beta expression in human testicular germ cell tumors.

Purpose: Estrogen exposure has been linked to a risk for the development of testicular germ cell cancers. The effects of estrogen are now known to be mediated by estrogen receptor (ER)-alpha and -beta receptor subtypes, but only ER-beta has been found in human normal testis. The goal of the present study was to compare the localization and expression levels of these ER subtypes in testicular germ cell cancers (seminomas and nonseminomatous germ cell tumors) with normal testis.

Branched fatty acids in dairy and beef products markedly enhance alpha-methylacyl-CoA racemase expression in prostate cancer cells in vitro.

An enzyme previously identified as alpha-methylacyl-CoA racemase (AMACR) is overexpressed in high-grade prostatic intraepithelial neoplasia and in a majority (60-100%) of prostate cancers (CaPs) as compared with normal and benign hyperplastic lesions of the prostate, where it is minimally expressed. This enzyme is required for the beta-oxidation of branched-chain fatty acids, which include phytanic acid and its alpha-oxidation product, pristanic acid. Interestingly, there is an established correlation between CaP risk and the consumption of dairy and beef products, which also contain marked quantities of these two phytols.

Alpha-methylacyl-CoA racemase (P504S) expression in evolving carcinomas within benign prostatic hyperplasia and in cancers of the transition zone.

Carcinomas of the transition zone (TZ) constitute approximately 20% of all prostate cancers. The TZ is the site of origin of grade 1 and grade 2 cancers, the most well-differentiated of the Gleason grade tumors, as well as for benign prostatic hyperplasia (BPH). In this regard, grade 1 carcinoma has architectural features that closely mimic gland-rich BPH nodules.

Gene expression profiling of testosterone and estradiol-17 beta-induced prostatic dysplasia in Noble rats and response to the antiestrogen ICI 182,780.

We previously demonstrated that 1) treatment of Noble rats for 16 wk with testosterone (T) and estradiol-17 beta (E2) led to 100% incidence of dorsolateral prostate (DLP) dysplasia and hyperprolactinemia and 2) blockade of PRL release with bromocriptine cotreatment significantly lowered the incidence of DLP dysplasia. In the current study, we sought to determine whether E2 exerts direct effects, independent of PRL, in this model system. The pure antiestrogen ICI 182,780 (ICI), reported to have no effect on PRL release in female rats, was administered biweekly to T + E2-treated rats at 3 mg/kg body weight.

Expression of estrogen receptor beta in the fetal, neonatal, and prepubertal human prostate.

Background: Although androgens have long been implicated in the development, regulation, and pathophysiology of the prostate, evidence suggests that estrogens may also affect these processes. Specifically, estrogens have been shown to influence the development of the fetal and neonatal rodent prostate and to induce a pathognomonic change, termed squamous metaplasia, in the developing and adult prostate. Studies have been inconclusive, however, as to whether estrogens enhance or restrain the growth of the gland.