[Show abstract][Hide abstract] ABSTRACT: Evaluation of cancer genomes in global context is of great interest in light of changing ethnic distribution of the world population. We focused our study on men of African ancestry because of their disproportionately higher rate of prostate cancer (CaP) incidence and mortality. We present a systematic whole genome analyses, revealing alterations that differentiate African American (AA) and Caucasian American (CA) CaP genomes. We discovered a recurrent deletion on chromosome 3q13.31 centering on the LSAMP locus that was prevalent in tumors from AA men (cumulative analyses of 435 patients: whole genome sequence, 14; FISH evaluations, 101; and SNP array, 320 patients). Notably, carriers of this deletion experienced more rapid disease progression. In contrast, PTEN and ERG common driver alterations in CaP were significantly lower in AA prostate tumors compared to prostate tumors from CA. Moreover, the frequency of inter-chromosomal rearrangements was significantly higher in AA than CA tumors. These findings reveal differentially distributed somatic mutations in CaP across ancestral groups, which have implications for precision medicine strategies.
[Show abstract][Hide abstract] ABSTRACT: Androgen Receptor (AR) is the male hormone receptor and a nuclear transcription factor which plays a central role in the growth of normal and malignant prostate gland. Our earlier studies defined a mechanistic model for male hormone dependent regulation of AR protein levels in prostate cancer (CaP) cells through a negative feed-back loop between AR and PMEPA1, an androgen induced NEDD4 E3 ubiquitin ligase binding protein. This report focuses on the impact of PMEPA1 silencing on CaP biology. PMEPA1 knockdown accelerated the growth of CaP tumor cells in athymic nude mice. In cell culture models knockdown of PMEPA1 resulted in resistance to AR inhibitors enzalutamide and bicalutamide. While, AR protein down regulation by NEDD4 was PMEPA1 dependent, we also noted a PMEPA1 independent downregulation of PTEN by NEDD4. In a subset of human CaP, decreased PMEPA1 mRNA expression significantly correlated with increased levels of AR transcription target PSA, as a surrogate for elevated AR. This study highlights that silencing of PMEPA1 accelerates the growth of CaP cells through AR, NEDD4 and PTEN. Thus, the therapeutic restoration of PMEPA1 represents a promising complementary strategy correcting for AR and PTEN defects in CaP. Statement of significance: Here we define that silencing of PMEPA1 facilitates the growth of CaP cells and modulates AR through NEDD4 and PTEN. The restoration of PMEPA1 represents a promising complementary therapeutic strategy correcting for AR and PTEN defects.
[Show abstract][Hide abstract] ABSTRACT: Erythroblast transformation-specific-related gene (ERG) fusions, the most common and validated prostate cancer (CaP) genome alteration, result in alterations in the expression of the ERG oncoprotein. Significantly lower frequencies of ERG have been reported in tumors of African American (AA) in comparison to Caucasian American (CA) men. Building on our preliminary observations, this study has focused on the increased association of the ERG-negative status with higher-grade prostate tumors in AA men. Representative whole-mount prostate sections from a matched cohort of 63 AA and 63 CA men with Gleason scores of 4+3 and those with Gleason scores of 8-10 were analyzed for ERG oncoprotein by immunohistochemistry. The striking finding of this study was that ERG expression was 3 times more likely to be present in the higher-grade index tumors of CA men compared to AA men (31 of 63 vs. 10 of 63 patients, respectively; P<0.0001). Although the mechanisms underlying these differences have not been elucidated, the present study along with our previous observations underscores that ERG typing may enhance the understanding of ethnic differences and future targeted therapy of CaP.
Molecular and Clinical Oncology 11/2014; 2(6):982-986. DOI:10.3892/mco.2014.378
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Overexpression of ERG in the prostate epithelium, due to chromosomal translocations, contributes to prostate tumorigenesis. Here, genomic analysis of ERG siRNA-treated prostate cells harboring the endogenous TMPRSS2-ERG fusion revealed an inverse relationship between ERG and Annexin A2 (ANXA2) expression at both the RNA and protein level. ANXA2, a Ca(2+)-dependent and phospholipid-binding protein, is involved in various cellular functions, including maintenance of epithelial cell polarity. Mechanistic studies defined the prostate-specific transcription start site of ANXA2 and showed that the recruitment of ERG to the ANXA2 promoter is required for transcriptional repression by ERG. Knockdown of ERG enhanced the apical localization of ANXA2, the bundling of actin filaments at cell-cell junctions and formation of a polarized epithelial phenotype. ERG overexpression disrupted ANXA2-mediated cell polarity and promoted epithelial-mesenchymal transition (EMT) by inhibiting CDC42 and RHOA, and by activating cofilin. Immunohistochemistry demonstrated a reciprocal relationship of ANXA2 and ERG expression in a large fraction of primary prostate cancer clinical specimens. ANXA2 was absent or markedly reduced in ERG(+) tumors, which were mostly well differentiated. ERG(-) tumors, meanwhile, expressed moderate to high levels of ANXA2, and were either poorly differentiated or displayed subsets of poorly differentiated cells. Taken together, the transcriptional repression of ANXA2 by ERG in prostate epithelial cells plays a critical role in abrogating differentiation, promoting EMT, and in the reciprocal correlation of ERG and ANXA2 expression observed in human prostate cancer.
ANXA2 is a new component of the ERG network with potential to enhance biologic stratification and therapeutic targeting of ERG-stratified prostate cancers.
Molecular Cancer Research 10/2014; 13(2). DOI:10.1158/1541-7786.MCR-14-0275-T · 4.38 Impact Factor