2020
DOI: 10.1038/s41467-019-14219-6
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Abstract: Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differen… Show more

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Cited by 90 publications
(139 citation statements)
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References 69 publications
(177 reference statements)
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“…NEPC is one of most aggressive prostate cancers, with a median prognosis of only 7 months [3,4]. NEPC arises after salvage ADT as a result of (i) lineage plasticity, (ii) differentiation from adenocarcinoma to a neuroendocrine tumor, and (iii) escape from androgen receptor (AR) pathway inhibitation [5][6][7][8]. Therefore, early NEPC detection is necessary.…”
Section: Resultsmentioning
confidence: 99%
“…NEPC is one of most aggressive prostate cancers, with a median prognosis of only 7 months [3,4]. NEPC arises after salvage ADT as a result of (i) lineage plasticity, (ii) differentiation from adenocarcinoma to a neuroendocrine tumor, and (iii) escape from androgen receptor (AR) pathway inhibitation [5][6][7][8]. Therefore, early NEPC detection is necessary.…”
Section: Resultsmentioning
confidence: 99%
“…546,547 In addition, a model of MUC1-driven lineage plasticity in PCa shows that MUC1 can upregulate the expression of BRN2 by recruitment of MYC and subsequent binding to the promoter region of BRN2, which further contributes to SOX2 expression. 548,549 This series of molecular regulations indicates that MUC1 may act as an upstream effector to regulate SOX2-induced lineage plasticity of neuroendocrine trans-differentiation in PCa. 548 Finally, by integrating systemic analyses of GEMM with patient clinical data, Zou et al 550 provided conclusive genetic evidence that drug-induced neuroendocrine trans-differentiation of PCSCs is one of the main reasons behind treatment failure.…”
Section: Transition Between Non-csc and Csc States Definition And Chamentioning
confidence: 99%
“…548,549 This series of molecular regulations indicates that MUC1 may act as an upstream effector to regulate SOX2-induced lineage plasticity of neuroendocrine trans-differentiation in PCa. 548 Finally, by integrating systemic analyses of GEMM with patient clinical data, Zou et al 550 provided conclusive genetic evidence that drug-induced neuroendocrine trans-differentiation of PCSCs is one of the main reasons behind treatment failure. 551 Taken together, findings from different approaches, including clinical data, together with multiple in vitro and in vivo experimental models, strongly demonstrate that tumor cell plasticity-induced lineage switching enables PCa to escape from ARPI treatment.…”
Section: Transition Between Non-csc and Csc States Definition And Chamentioning
confidence: 99%
See 1 more Smart Citation
“…There were obvious features and hallmarks of NEPC incorporating (i) loss of AR signaling, p53 crosstalk, (ii) oncogenic reprogramming driven by master neural BRN2 transcription factor and (iii) elevated stemness traits associated with over-expressed SOX2 and EMT processes (11)(12)(13). Inhibition of PRAD self-renewal capacity and tumorigenicity signi cantly suppressed the tumor growth and NEPC differentiation process (14). Given that high hazards of relapse in PRAD has been attributed to the maintainance of PRAD stemness cells (PSC), possessing various stem cell properties that led to therapy resistance, there was an urgent to develop prognostic and/or predictive biomarkers associated with stemness.…”
Section: Introductionmentioning
confidence: 99%