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Featured researches published by Ron Firestein.


Cell | 2007

Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene

Jesse S. Boehm; Jean Zhao; Jun Yao; So Young Kim; Ron Firestein; Ian F. Dunn; Sarah K. Sjostrom; Levi A. Garraway; Stanislawa Weremowicz; Andrea L. Richardson; Heidi Greulich; Carly J. Stewart; Laura Mulvey; Rhine R. Shen; Lauren Ambrogio; Tomoko Hirozane-Kishikawa; David E. Hill; Marc Vidal; Matthew Meyerson; Jennifer K. Grenier; Greg Hinkle; David E. Root; Thomas M. Roberts; Eric S. Lander; Kornelia Polyak; William C. Hahn

The karyotypic chaos exhibited by human epithelial cancers complicates efforts to identify mutations critical for malignant transformation. Here we integrate complementary genomic approaches to identify human oncogenes. We show that activation of the ERK and phosphatidylinositol 3-kinase (PI3K) signaling pathways cooperate to transform human cells. Using a library of activated kinases, we identify several kinases that replace PI3K signaling and render cells tumorigenic. Whole genome structural analyses reveal that one of these kinases, IKBKE (IKKepsilon), is amplified and overexpressed in breast cancer cell lines and patient-derived tumors. Suppression of IKKepsilon expression in breast cancer cell lines that harbor IKBKE amplifications induces cell death. IKKepsilon activates the nuclear factor-kappaB (NF-kappaB) pathway in both cell lines and breast cancers. These observations suggest a mechanism for NF-kappaB activation in breast cancer, implicate the NF-kappaB pathway as a downstream mediator of PI3K, and provide a framework for integrated genomic approaches in oncogene discovery.


PLOS ONE | 2008

The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth

Ron Firestein; Gil Blander; Shaday Michan; Philipp Oberdoerffer; Shuji Ogino; Jennifer Campbell; Anupama Bhimavarapu; Sandra Luikenhuis; Rafael de Cabo; Charles S. Fuchs; William C. Hahn; Leonard Guarente; David A. Sinclair

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD+-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a β-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates β-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of β-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of β−catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in β−catenin-driven malignancies.


Nature | 2008

CDK8 is a colorectal cancer oncogene that regulates β-catenin activity

Ron Firestein; Adam J. Bass; So Young Kim; Ian F. Dunn; Serena J. Silver; Isil Guney; Ellen Freed; Azra H. Ligon; Natalie Vena; Shuji Ogino; Milan G. Chheda; Pablo Tamayo; Stephen Finn; Yashaswi Shrestha; Jesse S. Boehm; Supriya K Jain; Emeric Bojarski; Craig H. Mermel; Jordi Barretina; Jennifer A. Chan; José Baselga; Josep Tabernero; David E. Root; Charles S. Fuchs; Massimo Loda; Ramesh A. Shivdasani; Matthew Meyerson; William C. Hahn

Aberrant activation of the canonical WNT/β-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival. Although dysregulated β-catenin activity drives colon tumorigenesis, further genetic perturbations are required to elaborate full malignant transformation. To identify genes that both modulate β-catenin activity and are essential for colon cancer cell proliferation, we conducted two loss-of-function screens in human colon cancer cells and compared genes identified in these screens with an analysis of copy number alterations in colon cancer specimens. One of these genes, CDK8, which encodes a member of the mediator complex, is located at 13q12.13, a region of recurrent copy number gain in a substantial fraction of colon cancers. Here we show that the suppression of CDK8 expression inhibits proliferation in colon cancer cells characterized by high levels of CDK8 and β-catenin hyperactivity. CDK8 kinase activity was necessary for β-catenin-driven transformation and for expression of several β-catenin transcriptional targets. Together these observations suggest that therapeutic interventions targeting CDK8 may confer a clinical benefit in β-catenin-driven malignancies.


Cancer Cell | 2013

Oncogenic ERBB3 Mutations in Human Cancers

Bijay S. Jaiswal; Noelyn M. Kljavin; Eric Stawiski; Emily Chan; Chaitali Parikh; Steffen Durinck; Subhra Chaudhuri; Kanan Pujara; Joseph Guillory; Kyle A. Edgar; Vasantharajan Janakiraman; Rolf-Peter Scholz; Krista K. Bowman; Maria N. Lorenzo; Hong Li; Jiansheng Wu; Wenlin Yuan; Brock A. Peters; Zhengyan Kan; Jeremy Stinson; Michelle Mak; Zora Modrusan; Charles Eigenbrot; Ron Firestein; Howard M. Stern; Krishnaraj Rajalingam; Gabriele Schaefer; Mark Merchant; Mark X. Sliwkowski; Frederic J. de Sauvage

The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ~11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression in vivo.


Cancer Research | 2013

A Novel Tankyrase Small-Molecule Inhibitor Suppresses APC Mutation–Driven Colorectal Tumor Growth

Ted Lau; Emily Chan; Marinella Callow; Jo Waaler; Jason Boggs; Robert A. Blake; Steven Magnuson; Amy Sambrone; Melissa Schutten; Ron Firestein; Ondrej Machon; Vladimir Korinek; Edna F. Choo; Mark Merchant; Paul Polakis; Daniel Holsworth; Stefan Krauss; Mike Costa

Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin-mediated signaling. However, continued requirement of Wnt/β-catenin signaling for tumor progression in the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-molecule tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt/β-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approximately 50% inhibition of APC mutation-driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic.


Proceedings of the National Academy of Sciences of the United States of America | 2003

Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase

Soo-A Kim; Panayiotis O. Vacratsis; Ron Firestein; Michael L. Cleary; Jack E. Dixon

The myotubularin (MTM) family constitutes one of the most highly conserved protein-tyrosine phosphatase subfamilies in eukaryotes. MTM1, the archetypal member of this family, is mutated in X-linked myotubular myopathy, whereas mutations in the MTM-related (MTMR)2 gene cause the type 4B1 Charcot–Marie-Tooth disease, a severe hereditary motor and sensory neuropathy. In this study, we identified a protein that specifically interacts with MTMR2 but not MTM1. The interacting protein was shown by mass spectrometry to be MTMR5, a catalytically inactive member of the MTM family. We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization. This article demonstrates an active MTM member being regulated by an inactive family member.


Molecular and Cellular Biology | 2000

Set domain-dependent regulation of transcriptional silencing and growth control by SUV39H1, a mammalian ortholog of Drosophila Su(var)3-9.

Ron Firestein; Xiangmin Cui; Phil Huie; Michael L. Cleary

ABSTRACT Mammalian SET domain-containing proteins define a distinctive class of chromatin-associated factors that are targets for growth control signals and oncogenic activation. SUV39H1, a mammalian ortholog ofDrosophila Su(var)3-9, contains both SET and chromo domains, signature motifs for proteins that contribute to epigenetic control of gene expression through effects on the regional organization of chromatin structure. In this report we demonstrate that SUV39H1 represses transcription in a transient transcriptional assay when tethered to DNA through the GAL4 DNA binding domain. Under these conditions, SUV39H1 displays features of a long-range repressor capable of acting over several kilobases to silence basal promoters. A possible role in chromatin-mediated gene silencing is supported by the localization of exogenously expressed SUV39H1 to nuclear bodies with morphologic features suggestive of heterochromatin in interphase cells. In addition, we show that SUV39H1 is phosphorylated specifically at the G1/S cell cycle transition and when forcibly expressed suppresses cell growth. Growth suppression as well as the ability of SUV39H1 to form nuclear bodies and silence transcription are antagonized by the oncogenic antiphosphatase Sbf1 that when hyperexpressed interacts with the SET domain and stabilizes the phosphorylated form of SUV39H1. These studies suggest a phosphorylation-dependent mechanism for regulating the chromatin organizing activity of a mammalian su(var) protein and implicate the SET domain as a gatekeeper motif that integrates upstream signaling pathways to epigenetic regulation and growth control.


Modern Pathology | 2009

SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer

Katsuhiko Nosho; Kaori Shima; Natsumi Irahara; Shoko Kure; Ron Firestein; Yoshifumi Baba; Saori Toyoda; Li Chen; Aditi Hazra; Edward Giovannucci; Charles S. Fuchs; Shuji Ogino

The class III histone deacetylase SIRT1 (sir2) is important in epigenetic gene silencing. Inhibition of SIRT1 reactivates silenced genes, suggesting a possible therapeutic approach of targeted reversal of aberrantly silenced genes. In addition, SIRT1 may be involved in the well-known link between obesity, cellular energy balance and cancer. However, a comprehensive study of SIRT1 using human cancer tissue with clinical outcome data is currently lacking, and its prognostic significance is uncertain. Using the database of 485 colorectal cancers in two independent prospective cohort studies, we detected SIRT1 overexpression in 180 (37%) tumors by immunohistochemistry. We examined its relationship to the CpG island methylator phenotype (CIMP), related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by MethyLight. SIRT1 overexpression was associated with CIMP-high (≥6 of 8 methylated CIMP-specific promoters, P=0.002) and microsatellite instability (MSI)-high phenotype (P<0.0001). In both univariate and multivariate analyses, SIRT1 overexpression was significantly associated with the CIMP-high MSI-high phenotype (multivariate odds ratio, 3.20; 95% confidence interval, 1.35–7.59; P=0.008). In addition, mucinous component (P=0.01), high tumor grade (P=0.02), and fatty acid synthase overexpression (P=0.04) were significantly associated with SIRT positivity in multivariate analysis. SIRT1 was not significantly related with age, sex, tumor location, stage, signet ring cells, cyclooxygenase-2 (COX-2), LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53, β-catenin, COX-2, or patient prognosis. In conclusion, SIRT1 expression is associated with CIMP-high MSI-high colon cancer, suggesting involvement of SIRT1 in gene silencing in this unique tumor subtype.


Nature | 2016

Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function

Elaine E. Storm; Steffen Durinck; Felipe de Sousa e Melo; Jarrod Tremayne; Noelyn M. Kljavin; Christine Tan; Xiaofen Ye; Cecilia Chiu; Thinh Pham; Jo-Anne Hongo; Travis W. Bainbridge; Ron Firestein; Elizabeth Blackwood; Ciara Metcalfe; Eric Stawiski; Robert L. Yauch; Yan Wu; Frederic J. de Sauvage

Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.


International Journal of Cancer | 2010

CDK8 Expression in 470 Colorectal Cancers in Relation to β- Catenin Activation, Other Molecular Alterations and Patient Survival

Ron Firestein; Kaori Shima; Katsuhiko Nosho; Natsumi Irahara; Yoshifumi Baba; Emeric Bojarski; Edward Giovannucci; William C. Hahn; Charles S. Fuchs; Shuji Ogino

Alterations in the Wnt/β‐catenin pathway define a key event in the pathogenesis of colon cancer. We have recently shown that CDK8, the gene encoding a cyclin‐dependent kinase (CDK) component of the Mediator complex, acts as a colon cancer oncogene that is necessary for β‐catenin activity. Here, we tested the hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes. Among 470 colorectal cancers identified in 2 prospective cohort studies, CDK8 expression was detected in 329 (70%) tumors by immunohistochemistry. Cox proportional hazards model and backward stepwise elimination were used to compute hazard ratio (HR) of deaths according to CDK8 status, initially adjusted for various patient and molecular features, including β‐catenin, p53, p21, p27 (CDK inhibitors), cyclin D1, fatty acid synthase (FASN), cyclooxygenase‐2 (COX‐2), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE‐1 methylation, and mutations in KRAS, BRAF and PIK3CA. CDK8 expression in colorectal cancer was independently associated with β‐catenin activation (p = 0.0002), female gender (p < 0.0001) and FASN overexpression (p = 0.0003). Among colon cancer patients, CDK8 expression significantly increased colon cancer‐specific mortality in both univariate analysis [HR 1.70; 95% confidence interval (CI), 1.03–2.83; p = 0.039] and multivariate analysis (adjusted HR 2.05; 95% CI, 1.18–3.56; p = 0.011) that was adjusted for potential confounders including β‐catenin, COX‐2, FASN, LINE‐1 hypomethylation, CIMP and MSI. CDK8 expression was unrelated with clinical outcome among rectal cancer patients. These data support a potential link between CDK8 and β‐catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis.

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William C. Hahn

Translational Genomics Research Institute

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Ian F. Dunn

Brigham and Women's Hospital

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