Concordant loss of fragile gene expression early in breast cancer development

Güler, Gülnur; Üner, Ayşegül; Güler, Nilüfer; Han, Sun‐Young; Iliopoulos, Dimitrios; McCue, Peter A.; Huebner, Kay

doi:10.1111/j.1440-1827.2005.01855.x

Cited by 68 publications

(70 citation statements)

References 28 publications

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“…The current findings suggest that WWOX changes are early events during OSCC development, a finding previously reported in breast carcinogenesis. 34,35 WWOX gene underexpression in human cancers could result from distinct events such as allelic losses, point mutations, promoter hypermethylation, aberrant mRNA transcription, or a combination of two or more events resulting in a loss of tumor suppressor activity. 36 Point mutations are rare in WWOX gene 28 but loss of heterozygosity of WWOX allele is observed in a variety of cancers.…”

Section: Discussionmentioning

confidence: 99%

Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias

et al. 2008

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SummaryOral leukoplakia is the most prevalent and potentially malignant disorder of the oral mucosa. Previous studies have demonstrated that molecular changes of the WWOX gene (WW-domain containing oxidoreductase), a candidate tumor suppressor gene located at 16q23.3-24.1 that spans FRA16D, the second most common fragile site, are present in several malignant neoplasias, including oral squamous cell carcinoma. In this report, the role of the WWOX gene was investigated in 23 cases of oral leukoplakias. Using nested RT-PCR and immunohistochemistry, altered mRNA transcription and/or reduced Wwox protein expression was observed in 35% of the lesions when compared with normal mucosa. The majority of lesions (4/6) with altered transcripts had a reduction in the expression of Wwox protein. Although normal WWOX expression was found in some lesions with dysplasia, all lesions with WWOX mRNA and/or protein expression showed histological evidence of dysplasia and none of the cases without dysplasia presented this alteration. These results show that the WWOX gene alteration is an early genetic alteration and may contribute to oral carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias

et al. 2008

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“…In fact, Rasmediated transformation of Wwox-KO MEFs results in an increased number of tumorigenic cells compared with WT cells, suggesting that WWOX deficiency facilitates transformation (60). Deletion or attenuation of WWOX is observed in early preneoplastic breast lesions (61,62) and targeted ablation of murine Wwox-associated mammary tumor formation (16). It is, thus, likely that loss of WWOX at early stages of neoplasia acts as a driver of the transformation process through compromising genome stability.…”

Section: Discussionmentioning

confidence: 99%

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Abu-Odeh

Salah

Herbel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

122

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Genomic instability is a hallmark of cancer. The WW domaincontaining oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.genomic instability | common fragile sites | WW domain-containing oxidoreductase | ataxia telangiectasia-mutated | ITCH G enomic instability is a common characteristic of human cancers. The DNA damage response (DDR) maintains the integrity of the genome in response to DNA damage. DDR is a complex signaling process that results in cell cycle arrest followed by either DNA repair or apoptosis if the DNA damage is too extensive to be repaired (1-3). Key mammalian damage response sensors are ataxia telangiectasia-mutated (ATM), ATM and Rad3-related, and DNA-dependent PKs (4, 5). Disruption of the DDR machinery in human cells leads to genomic instability and an increased risk of cancer progression (6, 7).The WW domain-containing oxidoreductase (WWOX) gene spans the common fragile site (CFS) FRA16D (8, 9). Genomic alterations affecting the WWOX locus have been reported in several types of cancer and include homozygous and hemizygous deletions (10-13). Ectopic expression of WWOX in WWOXnegative cancer cells attenuates cell growth and suppresses tumor growth in immunocompromised mice (10,11,14). Importantly, targeted ablation of Wwox in mice results in higher incidence of spontaneous lesions resembling osteosarcomas and lung and mammary tumors (14-16). These findings suggest WWOX as a tumor suppressor. The WWOX protein contains two Nterminal WW domains mediating WWOX interaction with PP(proline)x(amino acid)Y(tyrosine)-containing proteins (11, 17) and a central short-chain deyhdrogenase/reductase domain that has been proposed to function in steroidogenesis (18). Recent characterization of WWOX domains revealed that they interact, mainly through the WW1 domain, with multiprotein networks (3). The mechanism by which WWOX suppresses tumorigenicity is, however, not well-known.In vitro, CFSs are defined as gaps or breaks on metaphase chromosomes that occur in cells treated with inhibitors of DNA replication (19,20). In vivo, CFSs are preferential targets of replication stress in preneoplastic lesions (21), and emerging evidence suggests that they represent early warning sensors for DNA damage (22-24). ...

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“…The genetic events leading to high b-catenin activity in breast cancer have not yet been elucidated. We hypothesized that the lack of WWOX expression, which is frequent in breast cancer tissues (Driouch et al, 2002;Guler et al, 2004Guler et al, , 2005Chang et al, 2005), might constitutively stimulate the Wnt/b-catenin pathway and thereby contribute to enhancing tumor growth. Our observation that knockdown of WWOX enhances Wnt-3a transcriptional activity, as well as that WWOX overexpression inhibits Dvl-1 transcriptional activity in MCF-7 and BT474 cells, supports this hypothesis.…”

Section: Functional Interaction Between Wwox and Wnt Pathway N Bouteimentioning

confidence: 99%

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

et al. 2009

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The WWOX gene encodes a candidate tumor suppressor protein (WWOX) implicated in a variety of human diseases such as cancer. To better understand the molecular mechanisms of WWOX action, we investigated novel partners of this protein. Using the two-hybrid system and a coimmunoprecipitation assay, we observed a physical association between WWOX and the Dishevelled protein (Dvl) family signaling elements involved in the Wnt/b-catenin pathway. We found that enforced WWOX expression inhibited, and inhibition of endogenous WWOX expression stimulated the transcriptional activity of the Wnt/b-catenin pathway. Inhibition of endogenous WWOX expression also enhanced the effect of Wnt-3a on b-catenin stability. Moreover, we observed the sequestration of Dvl-2 wild type and Dvl-2NESm, a mutated form of Dvl-2 predominantly localized in the nucleus, in the cytoplasm compartment by WWOX. Our results indicate that WWOX is a novel inhibitor of the Wnt/b-catenin pathway. WWOX would act, at least in part, by preventing the nuclear import of the Dvl proteins.

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Concordant loss of fragile gene expression early in breast cancer development

Cited by 68 publications

References 28 publications

Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias

Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

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