Relation of ETS transcription factor family member ERG, androgen receptor and topoisomerase 2β expression to TMPRSS2-ERG fusion status in prostate cancer

Kolář, Zdeněk; Burdova, A.; Jamaspishvili, Tamara; Bouchal, Jan; Kučerová, Renata; Bienová, Martina; Král, Milan; Student, V.

doi:10.4149/neo_2014_004

Cited by 11 publications

(12 citation statements)

References 16 publications

(28 reference statements)

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“…In a subset of patients (N = 12, Kolar et al., 2014), presence of the chromosomal rearrangement at 21q22 was evaluated by interphase fluorescence in situ hybridization using Poseidon TMPRSS2‐ERG (21q22) Del, Break, TC Probe (Kreatech Diagnostics). Additional patients were evaluated by quantitative PCR.…”

Section: Methodsmentioning

confidence: 99%

DNA damage signalling barrier, oxidative stress and treatment‐relevant DNA repair factor alterations during progression of human prostate cancer

et al. 2016

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The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector. The DNA damage checkpoint barrier (γH2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8-oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression-opposing tumour suppressor role. TMPRSS2-ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP.

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Section: Methodsmentioning

confidence: 99%

DNA damage signalling barrier, oxidative stress and treatment‐relevant DNA repair factor alterations during progression of human prostate cancer

et al. 2016

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“…To this end, we identified non-ARE (whole or half) ARBS found in LNCaP[Src527F] but not in DHT-treated LNCaP cells. The three most prevalent of these non-canonical binding sites, which represent about 18-20% of all the ARBS, also contained potential binding motifs for FOXO1, topoisomerase IIβ (TOP2B) and ZNF217, all of which are known to contribute to AR-dependent CRPC growth [105, 106, 87]. ZNF217 and TOP2B expression is upregulated in human CRPC whereas that of FOXO1 is lost, mostly resulting from deep deletions.…”

Section: Discussionmentioning

confidence: 99%

Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures

et al. 2016

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Progression of prostate cancer (PC) to castration-recurrent growth (CRPC) remains dependent on sustained expression and transcriptional activity of the androgen receptor (AR). A major mechanism contributing to CRPC progression is through the direct phosphorylation and activation of AR by Src-family (SFK) and ACK1 tyrosine kinases. However, the AR-dependent transcriptional networks activated by Src during CRPC progression have not been elucidated. Here, we show that activated Src (Src527F) induces androgen-independent growth in human LNCaP cells, concomitant with its ability to induce proliferation/survival genes normally induced by dihydrotestosterone (DHT) in androgen-dependent LNCaP and VCaP cells. Src induces additional gene signatures unique to CRPC cell lines, LNCaP-C4-2 and CWR22Rv1, and to CRPC LuCaP35.1 xenografts. By comparing the Src-induced AR-cistrome and/or transcriptome in LNCaP to those in CRPC and LuCaP35.1 tumors, we identified an 11-gene Src-regulated CRPC signature consisting of AR-dependent, AR binding site (ARBS)-associated genes whose expression is altered by DHT in LNCaP[Src527F] but not in LNCaP cells. The differential expression of a subset (DPP4, BCAT1, CNTNAP4, CDH3) correlates with earlier PC metastasis onset and poorer survival, with the expression of BCAT1 required for Src-induced androgen-independent proliferation. Lastly, Src enhances AR binding to non-canonical ARBS enriched for FOXO1, TOP2B and ZNF217 binding motifs; cooperative AR/TOP2B binding to a non-canonical ARBS was both Src- and DHT-sensitive and correlated with increased levels of Src-induced phosphotyrosyl-TOP2B. These data suggest that CRPC progression is facilitated via Src-induced sensitization of AR to intracrine androgen levels, resulting in the engagement of canonical and non-canonical ARBS-dependent gene signatures.

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“…Although ERG overexpression is a rare event in nonneoplastic prostate tissue, most prostate cancer patients with TMPRSS2-ERG fusion have ERG overexpression [8,16,24,25]. The incidence of ERG overexpression and gene fusion was 42% and 31%, respectively.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of ERG rearrangement subtype and its association with increased p53 expression in Japanese and German prostate cancer

Nishijima¹,

Hara²,

Ikemoto³

et al. 2015

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Relation of ETS transcription factor family member ERG, androgen receptor and topoisomerase 2β expression to TMPRSS2-ERG fusion status in prostate cancer

Cited by 11 publications

References 16 publications

DNA damage signalling barrier, oxidative stress and treatment‐relevant DNA repair factor alterations during progression of human prostate cancer

DNA damage signalling barrier, oxidative stress and treatment‐relevant DNA repair factor alterations during progression of human prostate cancer

Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures

Clinical significance of ERG rearrangement subtype and its association with increased p53 expression in Japanese and German prostate cancer

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