The standard systemic treatment for prostate cancer (PCa) is androgen ablation, which causes tumor regression by inhibiting activity of the androgen receptor (AR). Invariably, PCa recurs with a fatal androgen-refractory phenotype. Importantly, the growth of androgen-refractory PCa remains dependent on the AR through various mechanisms of aberrant AR activation. Here, we studied the 22Rv1 PCa cell line, which was derived from a CWR22 xenograft that relapsed during androgen ablation. Three AR isoforms are expressed in 22Rv1 cells: a full-length version with duplicated exon 3 and two truncated versions lacking the COOH terminal domain (CTD). We found that CTD-truncated AR isoforms are encoded by mRNAs that have a novel exon 2b at their 3 ¶ end. Functionally, these AR isoforms are constitutively active and promote the expression of endogenous AR-dependent genes, as well as the proliferation of 22Rv1 cells in a ligand-independent manner. AR mRNAs containing exon 2b and their protein products are expressed in commonly studied PCa cell lines. Moreover, exon 2b-derived species are enriched in xenograft-based models of therapy-resistant PCa. Together, our data describe a simple and effective mechanism by which PCa cells can synthesize a constitutively active AR and thus circumvent androgen ablation. [Cancer Res 2008;68(13):5469-77]

Androgens, acting through the androgen receptor (AR), are responsible for the development of the male phenotype during embryogenesis, the achievement of sexual maturation at puberty, and the maintenance of male reproductive function and behavior in adulthood. In addition, androgens affect a wide variety of nonreproductive tissues. Moreover, aberrant androgen action plays a critical role in multiple pathologies, including prostate cancer and androgen insensitivity syndromes. The formation of a productive AR transcriptional complex requires the functional and structural interaction of the AR with its coregulators. In the last decade, an overwhelming and ever increasing number of proteins have been proposed to possess AR coactivating or corepressing characteristics. Intriguingly, a vast diversity of functions has been ascribed to these proteins, indicating that a multitude of cellular functions and signals converge on the AR to regulate its function. The current review aims to provide an overview of the AR coregulator proteins identified to date and to propose a classification of these AR coregulator proteins according to the function(s) ascribed to them. Taken together, this approach will increase our understanding of the cellular pathways that converge on the AR to ensure an appropriate transcriptional response to androgens.

The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, progression to castration-resistant prostate cancer (CRPC) typically follows and is largely the result of restored androgen signaling. Efforts to understand the mechanisms behind CRPC have revealed new insights into dysregulated androgen signaling and intratumoral androgen synthesis, which has ultimately led to the development of several novel androgen receptor (AR)-directed therapies for CRPC. However, emergence of resistance to these newer agents has also galvanized new directions in investigations of prereceptor and postreceptor AR regulation. Here, we review our current understanding of AR signaling as it pertains to the biology and natural history of prostate cancer.

Background Next-generation sequencing is revealing genomic heterogeneity in localized prostate cancer (CaP). Incomplete sampling of CaP multiclonality has limited the implications for molecular subtyping, stratification, and systemic treatment. Objective To determine the impact of genomic and transcriptomic diversity within and among intraprostatic CaP foci on CaP molecular taxonomy, predictors of progression, and actionable therapeutic targets. Design, setting, and participants Four consecutive patients with clinically localized National Comprehensive Cancer Network intermediate- or high-risk CaP who did not receive neoadjuvant therapy underwent radical prostatectomy at Roswell Park Cancer Institute in June–July 2014. Presurgical information on CaP content and a customized tissue procurement procedure were used to isolate nonmicroscopic and noncontiguous CaP foci in radical prostatectomy specimens. Three cores were obtained from the index lesion and one core from smaller lesions. RNA and DNA were extracted simultaneously from 26 cores with ≥90% CaP content and analyzed using whole-exome sequencing, single-nucleotide polymorphism arrays, and RNA sequencing. Outcome measurements and statistical analysis Somatic mutations, copy number alternations, gene expression, gene fusions, and phylogeny were defined. The impact of genomic alterations on CaP molecular classification, gene sets measured in Oncotype DX, Prolaris, and Decipher assays, and androgen receptor activity among CaP cores was determined. Results and limitations There was considerable variability in genomic alterations among CaP cores, and between RNA- and DNA-based platforms. Heterogeneity was found in molecular grouping of individual CaP foci and the activity of gene sets underlying the assays for risk stratification and androgen receptor activity, and was validated in independent genomic data sets. Determination of the implications for clinical decision-making requires follow-up studies. Conclusions Genomic make-up varies widely among CaP foci, so care should be taken when making treatment decisions based on a single biopsy or index lesions. Patient summary We examined the molecular composition of individual cancers in a patient’s prostate. We found a lot of genetic diversity among these cancers, and concluded that information from a single cancer biopsy is not sufficient to guide treatment decisions.

No abstract

No abstract

Increased expression of fatty acid synthase (FAS) is observed in a clinically aggressive subset of various common cancers and interference with FAS oers promising opportunities for selective chemotherapeutic intervention. The mechanisms by which FAS expression is (up)-regulated in these tumors remain, however, largely unknown. Recently we demonstrated that in LNCaP prostate cancer cells FAS expression is markedly elevated by androgens via an indirect pathway involving sterol regulatory element-binding proteins (SREBPs). Here, we also show that growth factors such as EGF are able to stimulate FAS mRNA, protein and activity. Several observations also indicate that the eects of EGF on FAS expression are ultimately mediated by SREBPs. EGF stimulates SREBP-1c mRNA expression and induces an increase in mature nuclear SREBP-1. Moreover, in transient transfection studies EGF stimulates the transcriptional activity of a 178 bp FAS promoter fragment harboring a complex SREBP-binding site. Deletion or mutation of this binding site abolishes these eects and ectopic expression of dominant negative SREBP-1 inhibits FAS expression and induction in intact LNCaP cells. Given the frequent dysregulation of growth factor signaling in cancer and the key role of SREBP-1 in lipid homeostasis, growth factor-induced activation of the SREBP pathway is proposed as one of the mechanisms responsible for upregulation of lipogenic gene expression in a subset of cancer cells. Oncogene (2000) 19, 5173 ± 5181.

The cellular effects of androgens are mediated by a cognate receptor, the androgen receptor. Typically, the androgen receptor is viewed to exert its activity by binding to androgen response elements located in or near the promoter region of target genes, thereby directly affecting the expression of these genes. However, increasing evidence indicates that androgens may also indirectly influence the expression of genes that do not contain androgen response elements by modulating the activity of secondary transcription factors, mediating the expression of growth factors acting in a paracrine or autocrine fashion, or by inducing changes in the production of other hormones. These indirect effects of androgens can induce cascade-like actions and may play an important role in more complex processes involving coordinated responses of genes, cells, and organs. Previously, our laboratory has identified and characterized a novel indirect mechanism of androgen action involving proteolytical activation of the key lipogenic transcription factor sterol regulatory element-binding protein (SREBP), resulting in the coordinate up-regulation of entire cellular lipogenic pathways. Interestingly, activation of SREBPs by androgens occurs not only under normal physiological conditions but has also been observed in a growing number of pathologies, and more in particular in the setting of steroid-regulated cancers, where increased lipogenesis has been shown to have remarkable diagnostic and prognostic potential and is considered a prime target for novel therapeutic approaches. This review aims to analyze current insights into the molecular mechanism(s) underlying androgen activation of the SREBP pathway and to ascertain the extent to which this phenomenon can be generalized to androgen-responsive cell systems.