Characterization of Differential Gene Expression in Adrenocortical Tumors Harboring β-Catenin (CTNNB1) Mutations

Durand, José Carlos Garcia; Lampron, Antoine; Mazzuco, Tânia Longo; Chapman, Arnold; Bourdeau, Isabelle

doi:10.1210/jc.2010-2143

Cited by 54 publications

(42 citation statements)

References 19 publications

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“…The ACC cases in our cohort were clinically heterogenous but are separated from the ACA cohort on retrospective clinicomorphologic grounds. CTNNB1 mutations were a common finding on the molecular screen and consistent with previously reported findings 36, 37 . Beta-catenin mutations appeared modestly but not statistically enriched in ACC (39%) compared with ACA (20%) and control adrenal tissue (0%).…”

Section: Resultssupporting

confidence: 91%

Genomic and immunohistochemical analysis in human adrenal cortical neoplasia reveal beta-catenin mutations as potential prognostic biomarker

et al. 2015

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Evaluation for malignancy of the adrenal cortex, adrenal cortical carcinoma (ACC), is a challenge in surgical pathology due to its relative rarity and histologic overlap with its benign counterpart, adrenocortical adenoma (ACA). We characterized a cohort of human ACC and ACA, including a molecular screen, with a goal of identifying potential diagnostic adjuncts. Thirty-six cases of ACC underwent histologic and clinical review. In the 31 ACC cases with available material and a cohort of 10 ACA cases, a multiplex nucleotide amplification molecular screen from formalin-fixed, paraffin-embedded tissue was peformed. ACCs demonstrated a wide variety of clinical and histologic characteristics with overall poor but unpredictable survival for subjects with ACC. By mutational screen, 12/31 (38.7%) carcinomas harbored CTNNB1 mutations, 1 with an additional TP53 mutation; 1 case each had isolated APC and TP53 mutations; 16 were wild-type for all tested loci; and 1 case demonstrated repeated assay failures. Two of the 10 ACA (20%) demonstrated CTNNB1 mutations by mutational screen, with no additional mutations. Immunohistochemistry for beta-catenin was performed and compared with the results of the molecular screen. Strong nuclear beta-catenin immunopositivity corresponded to the presence of CTNNB1 mutation by genotyping in 10 of 12 cases (83% sensitivity); the mismatched case(s) demonstrated strong membranous staining by immunohistochemistry. Seventeen of the 18 cases without CTNNB1 mutation showed membranous staining or did not stain (94% specificity); the mismatched case demonstrated scattered (<10%) positive nuclei. Both mutations in ACA were corroborated with immunohistochemistry for beta-catenin. No histomorphologic parameter appeared dominant in lesions with a particular mutational status. Based on these results, mutational status of CTNNB1 in adrenal cortical neoplasms can be predicted with reasonable accuracy by immunohistochemical cellular localization. Nuclear localization of beta-catenin by immunostain may be helpful in analysis of select lesions of the adrenal cortex whose biological behavior is uncertain from clinical and histologic information; a larger cohort is required to test this hypothesis.

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Section: Resultssupporting

confidence: 91%

Genomic and immunohistochemical analysis in human adrenal cortical neoplasia reveal beta-catenin mutations as potential prognostic biomarker

et al. 2015

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“…This molecule has been shown to reduce the amount of b-catenin and to inhibit the transcriptional response to Wnt/b-catenin signalling in developing zebrafish and Xenopus embryos and larvae 28,29 , indicating its suitability for in vivo studies. In order to confirm endo-IWR-1 phenotypes, we used PNU-74654 that prevents the interaction between b-catenin and the transcription factor TCF 26,30 . Treatment with either molecule from 33 to 55 hpf allowed us to avoid interferences with earlier global functions of b-catenin 31 , and to specifically target the period during which cell proliferation reorganizes around the ventral midline and massive neural differentiation occurs.…”

Section: Resultsmentioning

confidence: 99%

Involvement of the Wnt/β-catenin pathway in neurectoderm architecture in Platynereis dumerilii

et al. 2013

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Signalling pathways are essential for the correct development of the central nervous system (CNS) in bilaterian animals. Here we show that in the CNS of the annelid Platynereis dumerilii, neural progenitor cells (NPCs) are located close to the ventral midline and express axin, a negative regulator of the Wnt/b-catenin pathway. Using pharmacological inhibitors, we observe that Wnt/b-catenin is required for the transition between proliferating NPCs and differentiating neurons. We also show that the Rho-associated kinase (Rok) is necessary for neurectoderm morphogenesis and ventral midline formation, and indirectly affects the distribution of the NPCs and the development of axonal scaffolds. Moreover, seven genes belonging to the planar cell polarity (PCP) pathway are expressed in the developing Platynereis neurectoderm, suggesting an involvement in its morphogenesis. When compared with previous studies in vertebrates, our data suggest that the involvement of the Wnt/b-catenin pathway in the control of neural cell proliferation/differentiation is ancestral to bilaterians.

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“…The WNT/β-catenin pathway has been shown to play an important role in ACC, with alteration of this pathway found in over 30% of ACC cases (22, 23). In canonical WNT/β-catenin signaling, β-catenin complexes with adenomatous polyposis coli, axin, and glycogen synthase kinase-3b (GSK3b) are subsequently phosphorylated and degraded.…”

Section: Discussionmentioning

confidence: 99%

Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma

Satoh

Zhang

et al. 2016

Clinical Cancer Research

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Purpose Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, and no current effective therapy is available for locally advanced and metastatic ACC. Drug repurposing is an emerging approach for identifying new indications for existing drugs, especially for rare cancers such as ACC. The objective of this study was to use quantitative high-throughput screening to identify agents with antineoplastic activity against ACC. Experimental Design A screening of 4,292 compounds was performed on three ACC cell lines: BD140A, SW-13, and NCI-H295R. Results Twenty-one active compounds were identified, with an efficacy of >80% in all three cell lines. Of these, niclosamide showed higher efficacy and lower IC50 than established anti-ACC drugs. We then validated niclosamide-inhibited cellular proliferation in all three ACC cell lines. Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G1 cell cycle arrest. Niclosamide also decreased cellular migration and reduced the level of mediators of epithelial-to-mesenchymal transition, such as N-cadherin and vimentin. Furthermore, niclosamide treatment resulted in decreased expression of β-catenin. We also evaluated the effect of niclosamide on energy metabolism in ACC cell lines and found it resulted in mitochondrial uncoupling. Niclosamide treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Conclusions Our findings suggest that niclosamide has anti-ACC activity through its inhibition of multiple altered cellular pathways and cellular metabolism in ACC. Our results provide a preclinical rationale for evaluating niclosamide therapy in a clinical trial for ACC.

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Characterization of Differential Gene Expression in Adrenocortical Tumors Harboring β-Catenin (CTNNB1) Mutations

Abstract: This study identified candidate genes deregulated in CTNNB1-mutated adrenocortical tumors that may lead to a better understanding of the role of the Wnt-β-catenin pathway in adrenocortical tumorigenesis.

Cited by 54 publications

References 19 publications

Genomic and immunohistochemical analysis in human adrenal cortical neoplasia reveal beta-catenin mutations as potential prognostic biomarker

Genomic and immunohistochemical analysis in human adrenal cortical neoplasia reveal beta-catenin mutations as potential prognostic biomarker

Involvement of the Wnt/β-catenin pathway in neurectoderm architecture in Platynereis dumerilii

Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma

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