Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal
ABSTRACT Synthesis of truncated androgen receptor (AR) splice variants has emerged as an important mechanism of prostate cancer (PCa) resistance to AR-targeted therapy and progression to a lethal castration-resistant phenotype. However, the precise role of these factors at this stage of the disease is not clear due to loss of multiple COOH-terminal AR protein domains, including the canonical nuclear localization signal (NLS) in the AR hinge region. Despite loss of this NLS, we show that diverse truncated AR variant species have a basal level of nuclear localization sufficient for ligand-independent transcriptional activity. Whereas full-length AR requires Hsp90 and importin-β for active nuclear translocation, basal nuclear localization of truncated AR variants is independent of these classical signals. For a subset of truncated AR variants, this basal level of nuclear import can be augmented by unique COOH-terminal sequences that reconstitute classical AR NLS activity. However, this property is separable from ligand-independent transcriptional activity. Therefore, the AR splice variant core consisting of the AR NH(2)-terminal domain and DNA binding domain is sufficient for nuclear localization and androgen-independent transcriptional activation of endogenous AR target genes. Indeed, we show that truncated AR variants with nuclear as well as nuclear/cytoplasmic localization patterns can drive androgen-independent growth of PCa cells. Together, our data demonstrate that diverse truncated AR species with varying efficiencies of nuclear localization can contribute to castration-resistant PCa pathology by driving persistent ligand-independent AR transcriptional activity.
- SourceAvailable from: Margarida Fardilha
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- "Moreover, it was recently shown that truncated forms of AR with intact NH 2 -terminal and DNA binding domains are constitutively active and able to maintain androgen-independent transcriptional activation of endogenous AR target genes, thus supporting androgen-independent growth of PCa cells (Chan et al., 2012). The expression of these forms is associated with a poor prognosis and they have been recognized Fig. 2 "
ABSTRACT: Prostate cancer (PCa) incidence and mortality have decreased in recent years. Nonetheless, it remains one of the most prevalent cancers in men, being a disquieting cause of men's death worldwide. Changes in many cell signaling pathways have a predominant role in the onset, development, and progression of the disease. These include prominent pathways involved in the growth, apoptosis, and angiogenesis of the normal prostate gland, such as androgen and estrogen signaling, and other growth factor signaling pathways. Understanding the foundations of PCa is leading to the discovery of key molecules that could be used to improve patient management. The ideal scenario would be to have a panel of molecules, preferably detectable in body fluids, that are specific and sensitive biomarkers for PCa. In the early stages, androgen deprivation is the gold standard therapy. However, as the cancer progresses, it eventually becomes independent of androgens, and hormonal therapy fails. For this reason, androgen-independent PCa is still a major therapeutic challenge. By disrupting specific protein interactions or manipulating the expression of some key molecules, it might be possible to regulate tumor growth and metastasis formation, avoiding the systemic side effects of current therapies. Clinical trials are already underway to assess the efficacy of molecules specially designed to target key proteins or protein interactions. In this review, we address that recent progress made towards understanding PCa development and the molecular pathways underlying this pathology. We also discuss relevant molecular markers for the management of PCa and new therapeutic challenges.Journal of Zhejiang University SCIENCE B 01/2014; 15(1):16-42. DOI:10.1631/jzus.B1300106 · 1.29 Impact Factor
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- "The biological and clinical significance of differential expression of isoform variants is illustrated, for example, by the bcl-2 apoptotic gene family member bcl-x , for which the short (xS) and long (xL) variants are pro-and antiapoptotic, respectively. In prostate cancer, one of the most clinically relevant examples of differential expression of isoform variants has only recently been characterized for the androgen receptor (AR)   . While expression of the main isoform variant of AR is tightly coupled to sensitivity to antiandrogen therapy (AAT), the truncated v567 variant functions as a constitutively active, ligandindependent transcription factor that can support androgenindependent growth and progression of castrate-resistant metastatic prostate cancer. "
ABSTRACT: Prostate cancer is a clinically and biologically heterogeneous disease. Deregulation of splice variants has been shown to contribute significantly to this complexity. High-throughput technologies such as oligonucleotide microarrays allow for the detection of transcripts that play a role in disease progression in a transcriptome-wide level. In this study, we use a publicly available dataset of normal adjacent, primary tumor, and metastatic prostate cancer samples (GSE21034) to detect differentially expressed coding and non-coding transcripts between these disease states. To achieve this, we focus on transcript-specific probe selection regions, that is, those probe sets that correspond unambiguously to a single transcript. Based on this, we are able to pinpoint at the transcript-specific level transcripts that are differentially expressed throughout prostate cancer progression. We confirm previously reported cases and find novel transcripts for which no prior implication in prostate cancer progression has been made. Furthermore, we show that transcript-specific differential expression has unique prognostic potential and provides a clinically significant source of biomarker signatures for prostate cancer risk stratification. The results presented here serve as a catalog of differentially expressed transcript-specific markers throughout prostate cancer progression that can be used as basis for further development and translation into the clinic.Journal of Oncology 08/2012; 2012:541353. DOI:10.1155/2012/541353
- Cancer Research 06/2012; 72(8 Supplement):2148-2148. DOI:10.1158/1538-7445.AM2012-2148 · 9.28 Impact Factor