Sergio Ruíz-Llorente

Hospital Universitario HM Sanchinarro

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Cristina Montero‐Conde

Spanish National Cancer Research Centre

María J. Barrero

Instituto de Salud Carlos III

Jacinto Sarmentero

Hospital Universitario 12 De Octubre

Verónica García-Carpizo

Spanish National Cancer Research Centre

James A. Fagin

Memorial Sloan Kettering Cancer Center

Mercedes Robledo

Centre for Biomedical Network Research on Rare Diseases

Ronald Ghossein

Memorial Sloan Kettering Cancer Center

Mabel Ryder

Mayo Clinic in Arizona

Jeffrey A. Knauf

Cleveland Clinic

Neal Rosen

Memorial Sloan Kettering Cancer Center

Cooperative Institutions

Spanish National Cancer Research Centre

Instituto de Salud Carlos III

Centro de Investigación del Cáncer

Centre for Biomedical Network Research on Rare Diseases

Universidad Autónoma de Madrid

UNSW Sydney

HM Hospitales

Hospital Universitario HM Sanchinarro

Centro de Investigación Biomédica en Red

University of Melbourne

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Data from Relief of Feedback Inhibition of HER3 Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in BRAF-Mutant Thyroid Carcinomas

Cristina Montero‐Conde Sergio Ruíz-Llorente José María Domínguez Jeffrey A. Knauf Agnès Viale

<div>AbstractThe RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. In contrast to melanomas, inhibition of mitogen-activated protein kinase (MAPK) signaling by PLX4032 is transient in thyroid and colorectal cancer cells. The rebound in extracellular signal-regulated kinase (ERK) in thyroid cells is accompanied by increased HER3 signaling caused by induction of ERBB3 (HER3) transcription through decreased promoter occupancy by the transcriptional repressors C-terminal binding protein 1 and 2 and by autocrine secretion of neuregulin-1 (NRG1). The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MAP-ERK kinase inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific receptor tyrosine kinases, and the abundance of their respective ligands.Significance: Thyroid cancer cell lines with mutant BRAF are resistant to PLX4032. RAF inhibitors transiently inhibit the ERK pathway and de-repress HER3 transcription. In the context of constitutive NRG1 secretion, this results in an ERK and AKT rebound that diminishes the antitumor effects of RAF inhibitors, which is overcome by combination with lapatinib. Cancer Discov; 3(5); 520–33. ©2013 AACR.See related commentary by Girotti and Marais, p. 487This article is highlighted in the In This Issue feature, p. 471</div>

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10.1158/2159-8290.c.6545915.v1

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Data from Association Study of 69 Genes in the Ret Pathway Identifies Low-penetrance Loci in Sporadic Medullary Thyroid Carcinoma

Sergio Ruíz-Llorente Cristina Montero‐Conde Roger L. Milne Christian M. Moya Arancha Cebrián

<div>AbstractTo date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium–based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases. [Cancer Res 2007;67(19):9561–7]</div>

Penetrance

Medullary carcinoma

Association (psychology)

10.1158/0008-5472.c.6496625.v1

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Molecular study of a new family with hereditary renal cell carcinoma and a translocation t(3;8)(p13;q24.1)

Human Genetics (2003)

Bárbara Meléndez Sandra Rodríguez Beatriz Martínez‐Delgado Ignacio Otero Mercedes Robledo

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Derivative chromosome

Chromosome 3

Folliculin

10.1007/s00439-002-0848-6

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Citations (23)

Alpha-Lipoic Acid Decreases Iodine Uptake in the Rat Thyroid Cell Line FRTL-5

Journal of Korean Thyroid Association (2012)

Ji Hye Yim Tae Yong Kim Sergio Ruíz-Llorente Won Gu Kim Ji Min Han

Background and Objectives Alpha-lipoic acid (ALA) is a naturally occurring fatty acid with strong antioxidant properties that exerts protective effects against harmful free radical damage. The aim of the present study was to assess the effect of ALA on iodine uptake and expression of sodium iodine symporter (NIS) using FRTL-5 cells. Materials and Methods Cells were treated with ALA for various time and doses, in the presence or absence of thyrotropin (TSH). Cell viability assay, iodine uptake assay and NIS promoter activity assay were performed. Results ALA increased NIS promoter activity. It showed an additive effect when concomitantly added with TSH. After 48 hours of incubation with ALA in the presence or absence of TSH, there was no difference in iodine uptake according to doses of ALA. After 72 hours of incubation with ALA and TSH, ALA decreased iodine uptake in dose-dependent way. Conclusion ALA induced NIS gene transcription of FRTL-5, but suppressed iodine uptake in the presence of TSH. ALA may suppress iodine uptake through effect for post-translation stage of NIS protein.

Sodium-iodide symporter

Viability assay

10.11106/jkta.2012.5.1.39

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Supplementary Methods and References from Relief of Feedback Inhibition of HER3 Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in BRAF-Mutant Thyroid Carcinomas

Cristina Montero‐Conde Sergio Ruíz-Llorente José María Domínguez Jeffrey A. Knauf Agnès Viale

Supplementary Methods and References PDF File - 39K, Supplementary Methods and References

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10.1158/2159-8290.22529369

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Supplementary Figure S4 from Relief of Feedback Inhibition of HER3 Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in BRAF-Mutant Thyroid Carcinomas

Cristina Montero‐Conde Sergio Ruíz-Llorente José María Domínguez Jeffrey A. Knauf Agnès Viale

Supplementary Figure S4 PDF file - 81K, Exogenous ligand-dependence of PLX4032-induced HER3 activation in melanoma cell lines. A, lysates of melanoma cell lines treated with 2 �gM PLX4032 for the indicated times were immunoblotted for tHER3. B, response of SK-MEL-28 cells to ligand induced activation of HER2/HER3 after exposure to PLX4032. Cells were treated with PLX4032 for 48 h, and then with or without 50 ng/ml of NRG1 for 5 minutes. RAS-GTP was detected by IP with RAS binding domain of CRAF (RBD) followed by Western blotting with anti-RAS. Input lysates were immunoblotted with the indicated antibodies. C, SK-MEL-28 cells were treated with increasing concentrations of PLX4032 alone (dark grey) or in combination with NRG1 (red). Cells were collected and counted after 4 days of treatment. Bars represent percent change (mean +/- SD) in cell counts of triplicate wells compared to untreated cells. *p < 0.05

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10.1158/2159-8290.22529381.v1

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Figure S1 from CREBBP/EP300 Bromodomain Inhibition Affects the Proliferation of AR-Positive Breast Cancer Cell Lines

Verónica García-Carpizo Sergio Ruíz-Llorente Jacinto Sarmentero Ana González‐Corpas María J. Barrero

Statistical analysis of growth competition assays (a) ANOVA diamond plots showing the adjusted % of inhibition at day 12 for gRNAs grouped into the indicated categories and considering three independent experiments. (b) Tukey-Kramer statistical test results of data shown in a. p-values<0.05 are highlighted in bold and considered significantly different from other categories.

Statistical Analysis

10.1158/1541-7786.22515891.v1

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Figure S6 from CREBBP/EP300 Bromodomain Inhibition Affects the Proliferation of AR-Positive Breast Cancer Cell Lines

Verónica García-Carpizo Sergio Ruíz-Llorente Jacinto Sarmentero Ana González‐Corpas María J. Barrero

Selection of potential target genes of CREBBP/EP300 bromodomain inhibitors in LNCaP. Genomic tracks showing the levels of H3K27ac, AR and mRNA levels in LNCaP cells surrounding known AR-target genes in LNCaP cells. Right insets correspond to magnifications of the genomic regions labeled in grey. Intervals corresponding to SEs are also shown.

MCF-7

10.1158/1541-7786.22515876

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Therapeutic potential of TAF1 bromodomains for cancer treatment

bioRxiv (Cold Spring Harbor Laboratory) (2018)

Verónica García-Carpizo Sergio Ruíz-Llorente Jacinto Sarmentero María J. Barrero

ABSTRACT The discovery of the antiproliferative effects of BRD4 bromodomain inhibitors prompted us to investigate additional bromodomains that might be involved in supporting cellular proliferation. TAF1 is a general transcription factor with two bromodomains that is likely to play important roles in cell viability by supporting transcription. Our work shows that knock down of TAF1 caused antiproliferative effects in several cancer cell lines. Using CRISPR-Cas9 editing techniques we demonstrate that the bromodomains of TAF1 are essential to maintain proliferation of K562 and H322 cells. BAY-299, the best TAF1 bromodomain inhibitor developed so far, also showed antiproliferative effects. BAY-299 caused discrete transcriptional changes that were likely on target but did not correlate with strong effects in cell cycle distribution suggesting that these effects might be, at least in part, mediated by another target. Compared to the TAF1 knock down, BAY-299 specifically downregulated the expression of genes with high levels of TAF1 and histone acetylation at their promoters, suggesting that targeting the bromodomains has distinct transcriptional effects than targeting the whole protein. This might help to provide a therapeutic window to target specifically cancer cells with high levels of histone acetylation at proliferation-related genes.

BRD4

TAF1

10.1101/394254

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Correction: An Epistatic Interaction between the PAX8 and STK17B Genes in Papillary Thyroid Cancer Susceptibility

PLoS ONE (2013)

Papillary Thyroid Cancer (PTC) is a heterogeneous and complex disease; susceptibility to PTC is influenced by the joint effects of multiple common, low-penetrance genes, although relatively few have been identified to date.Here we applied a rigorous combined approach to assess both the individual and epistatic contributions of genetic factors to PTC susceptibility, based on one of the largest series of thyroid cancer cases described to date.In addition to identifying the involvement of TSHR variation in classic PTC, our pioneer study of epistasis revealed a significant interaction between variants in STK17B and PAX8.The interaction was detected by MD-MBR (p = 0.00010) and confirmed by other methods, and then replicated in a second independent series of patients (MD-MBR p = 0.017).Furthermore, we demonstrated an inverse correlation between expression of PAX8 and STK17B in a set of cell lines derived from human thyroid carcinomas.Overall, our work sheds additional light on the genetic basis of thyroid cancer susceptibility, and suggests a new direction for the exploration of the inherited genetic contribution to disease using association studies.

Epistasis

PAX8

10.1371/annotation/cd94c3eb-70f2-4dfa-85be-b3fc41e495c3

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Citations (1)