Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate Cancer

Hu, Rong; Dunn, Thomas A.; Wei, Shuanzeng; Isharwal, Sumit; Veltri, Robert W.; Humphreys, Elizabeth B.; Han, Misop; Partin, Alan W.; Vessella, Robert L.; Isaacs, William B.; Bova, G. Steven; Luo, Jun

doi:10.1158/0008-5472.can-08-2764

Cited by 951 publications

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“…We only found the previously reported CE3-G allele in this population (data not shown). In addition, CE4 has been reported to code either an 11-amino acid or 53-amino acid peptide [9,11] depending on the presence of a stop codon (TAA) at codon 12 of the CE4-specific peptide (Fig. 3c).…”

Section: Novel and Known Single Nucleotide Polymorphisms In Ar Cryptimentioning

confidence: 99%

“…To determine whether these three ARVs are expressed in breast cancer cells, a forward primer at exon 6 was paired with a reverse primer P2(R) at exon 9 [11] to amplify the 6510-bp region encompassing exons 6-9 from MDA-MB-453-and VCaP-derived cDNA. Surprisingly, the results consistently revealed amplicons that were smaller than the expected 6510-bp PCR product.…”

Section: Identification Of Novel Exon 9-containing Splicing Variantsmentioning

confidence: 99%

“…Most ARVs have been shown to be constitutively (AR-V3, -V4, -V7, and -V12) [9,10,12,17] or conditionally (AR-V1 and -V9) [10,12] active androgen-independent transcription factors in a prostate cancer context. Pre-clinical and clinical studies have supported the concept that ARVs are biologically relevant in prostate cancer, particularly in the genesis of a CRPC [11,12,[17][18][19][20].…”

Section: Introductionmentioning

confidence: 97%

“…In addition, at least 7 other so-called "cryptic" exons (CE1-5, CE1b, and CE9) have been identified in the AR gene [9][10][11][12][13]. These cryptic exons can be incorporated into AR transcripts by altered splicing events [14] or as a result of genomic rearrangements [15,16], yielding at least 14 variant AR transcripts (termed AR-V1 to AR-V14) [10].…”

Section: Introductionmentioning

confidence: 99%

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Identification of Androgen Receptor Splice Variant Transcripts in Breast Cancer Cell Lines and Human Tissues

Hickey

Irvine

et al. 2014

HORM CANC

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The androgen receptor (AR) is widely expressed in human tissues and has biological function in many male and female organs. In particular, the AR plays a critical role in the biology and pathology of the prostate gland. AR activity inhibits breast growth and has pleiotropic actions in breast cancer that are subtype-dependent. Expression of AR splice variants (ARVs) and their role in prostate carcinogenesis has been elucidated in recent studies. We hypothesised that ARVs are also expressed in breast cancers and other hormone sensitive tissues. Herein, the expression of five previously identified ARV transcripts with documented transcriptional capacity (AR-V1, -V3, -V4, -V7, and -V9) was examined in 6 breast (MFM223, MDA-MB-453, MDA-MB-231, ZR75

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Section: Novel and Known Single Nucleotide Polymorphisms In Ar Cryptimentioning

confidence: 99%

Section: Identification Of Novel Exon 9-containing Splicing Variantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Identification of Androgen Receptor Splice Variant Transcripts in Breast Cancer Cell Lines and Human Tissues

Hickey

Irvine

et al. 2014

HORM CANC

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“…These house-keeping genes included GAPDH, HPRT1 and TFRC, which were previously used as controls for evaluating expression differences caused by surgical manipulation, 5 as well as SF3A3, an established control gene for Q-RT-PCR. 12 Gene oncology (GO) analysis GO analysis of the 75 genes presented in Figure 3a identified two molecular functions, transcription factor activity (GO: 0003700j 0000130) and oxygen transport (GO: 0015671), which were significantly enriched (adjusted P,0.05) in the 75-gene signature (Figure 4a and b). Notably, all of the 11 transcription factors enriched in the 'transcriptional factor activity' GO term have well-documented roles in mediating inflammatory or stress response in the literature.…”

Section: Surgical Type and Prostate Tumor Gene Expression J LI Et Al 710mentioning

confidence: 99%

Effect of surgical procedures on prostate tumor gene expression profiles

Li¹,

Zhang²,

Yin³

et al. 2012

Asian J Androl

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Current surgical treatment of prostate cancer is typically accomplished by either open radical prostatectomy (ORP) or robotic-assisted laparoscopic radical prostatectomy (RALRP). Intra-operative procedural differences between the two surgical approaches may alter the molecular composition of resected surgical specimens, which are indispensable for molecular analysis and biomarker evaluation. The objective of this study is to investigate the effect of different surgical procedures on RNA quality and genome-wide expression signature. RNA integrity number (RIN) values were compared between total RNA samples extracted from consecutive LRP (n511) and ORP (n524) prostate specimens. Expression profiling was performed using the Agilent human whole-genome expression microarrays. Expression differences by surgical type were analyzed by Volcano plot analysis and gene ontology analysis. Quantitative reverse transcription (RT)-PCR was used for expression validation in an independent set of LRP (n58) and ORP (n58) samples. The LRP procedure did not compromise RNA integrity. Differential gene expression by surgery types was limited to a small subset of genes, the number of which was smaller than that expected by chance. Unexpectedly, this small subset of differentially expressed genes was enriched for those encoding transcription factors, oxygen transporters and other previously reported surgery-induced stress-response genes, and demonstrated unidirectional reduction in LRP specimens in comparison to ORP specimens. The effect of the LRP procedure on RNA quality and genome-wide transcript levels is negligible, supporting the suitability of LRP surgical specimens for routine molecular analysis. Blunted in vivo stress response in LRP specimens, likely mediated by CO 2 insufflation but not by longer ischemia time, is manifested in the reduced expression of stress-response genes in these specimens. Asian Journal of Andrology (2012) 14, 708-714; doi:10.1038/aja.2012.54; published online 6 August 2012Keywords: CO 2 insufflation; expression microarray; laparoscopic radical prostatectomy; open radical prostatectomy; prostate cancer; stress response INTRODUCTION Currently, for men with localized prostate cancer, surgical resection of the prostatic tumor is most often accomplished by one of two surgical approaches, open radical prostatectomy (ORP) or robot-assisted laparoscopic radical prostatectomy (RALRP), with the latter operation being increasingly practiced in developed countries. In the United States, RALRP accounts for an estimated 80% of RP surgeries. 1 In China, while RALRP is rarely performed, a substantial percentage of RP surgeries are nevertheless performed minimally invasively, via traditional laparoscopic radical prostatectomy (LRP). LRP is quite similar to RALRP and involves similar surgical approaches and steps that are different from conventional ORP. 2 The principal distinctions in sequential surgical steps between LRP and ORP are illustrated in Figure 1. During LRP, the prostate is typically devascularized earlier by ...

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Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

et al. 2015

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IMPORTANCE We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown. OBJECTIVE To investigate whether AR-V7–positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men. DESIGN, SETTING, AND PARTICIPANTS We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men. MAIN OUTCOMES AND MEASURES We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates. PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone). RESULTS Of 37 taxane-treated patients enrolled. 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7–positive and AR-V7–negative men (41% vs 65%; P = .19) Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7–positive and AR-V7–negative patients. A significant interaction was observed between AR-V7 status and treatment type (P < .001). Clinical outcomes were superior with taxanes compared with enzalutamide or abiraterone therapy in AR-V7–positive men, whereas outcomes did not differ by treatment type in AR-V7–negative men. In AR-V7–positive patients. PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003). CONCLUSIONS AND RELEVANCE Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7–positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7–negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell–based AR-V7 detection may serve as a treatment selection biomarker in CRPC.

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Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate Cancer

Abstract: Suppression of androgen production and function provides palliation but not cure in men with prostate cancer (PCa

Cited by 951 publications

References 18 publications

Identification of Androgen Receptor Splice Variant Transcripts in Breast Cancer Cell Lines and Human Tissues

Identification of Androgen Receptor Splice Variant Transcripts in Breast Cancer Cell Lines and Human Tissues

Effect of surgical procedures on prostate tumor gene expression profiles

Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

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