Frequent loss of WWOX expression in breast cancer: correlation with estrogen receptor status

Nunez, María I.; Ludes-Meyers, John; Abba, Martı́n C.; Kil, Hyunsuk; Abbey, Nancy W.; Page, Robert E.; Şahin, Ayşegül; Klein‐Szanto, Andres J.; Aldaz, C. Marcelo

doi:10.1007/s10549-004-1474-x

Cited by 90 publications

(107 citation statements)

References 11 publications

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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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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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“…Resting and lactating female breast-In the resting female breast both, the ductal luminal cells and myoepithelial cells were consistently positive for WWOX protein expression (Nunez et al 2005a). The lactating breast epithelium was strongly positive for WWOX expression in both ductal and acinar cells.…”

Section: Wwox Expression In Female Reproductive Systemmentioning

confidence: 99%

WWOX protein expression in normal human tissues

2006

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WWOX is a putative tumor suppressor gene that spans approximately a 1 Mb genomic region and is the site for the second most common chromosomal fragile site, FRA16D at 16q23. Various studies have focused on the expression of WWOX in human cancer mostly at the RNA level, but little is known about the normal pattern of WWOX protein expression in nonneoplastic tissues. In this study, a comprehensive analysis of WWOX protein expression in normal tissues was performed by means of immunohistochemistry utilizing a very specific anti-WWOX polyclonal antibody. We analyzed tissue cores of human samples representing more than 30 organs, using various tissue microarray (TMA) slides. Due to the potential role of WWOX in sex-steroid metabolism, whole sections from hormonally regulated organs like breast, ovaries, testes and prostate were also analyzed. The results from our study indicate that WWOX is preferentially highly expressed in secretory epithelial cells of reproductive, endocrine and exocrine organs, as well as in ductal epithelial cells from specific segments of the urinary system. Interestingly, we also observed significant WWOX protein expression in various cell types of neural origin including neurons, ependymal cells and astrocytes. No expression of WWOX was detected in adipose, connective, and lymphoid tissues, myelinized structures and blood vessels. By better defining the topographic distribution of WWOX in normal tissues this study provides some insight on the potential physiological role of this novel protein.

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“…Indeed, expression of WWOX is deregulated in twothirds of breast cancer cases (Guler et al, 2005;Nunez et al, 2005). We and others have recently reported that WWOX loss is a frequent event in breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR) and HER2 (triple negative (Sorlie et al, 2001)) and that loss of WWOX expression is associated with nodal metastasis and unfavorable outcome (Aqeilan et al, 2007a;Guler et al, 2009)).…”

Section: Introductionmentioning

confidence: 99%

Wwox inactivation enhances mammary tumorigenesis

et al. 2011

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Breast cancer is the leading cause of cancer-related death in women worldwide. Expression of the WWOX tumor suppressor is absent or reduced in a large proportion of breast tumors suggesting that loss of WWOX may contribute to breast tumorigenesis. Wwox-deficient mice die by 3-4 weeks of age precluding adult tumor analysis. To evaluate the effect of WWOX-altered expression on mammary tumor formation, the Wwox-heterozygous allele was back crossed onto the C3H mammary tumor-susceptible genetic background (Wwox C3H þ /À) and incidence of mammary tumor formation was evaluated. Although 50% of the female Wwox C3H þ /À mice developed mammary carcinomas, only 7% of Wwox C3H þ / þ mice did. Intriguingly, mammary tumors in Wwox C3H þ /À mice frequently lost WWOX protein expression suggesting a genetic predisposition toward mammary tumorigenesis. Immunohistochemical staining of hormone receptors revealed loss of estrogen receptor-a (ER) and progesterone receptor in the majority of these tumors. In vitro, depletion of WWOX in MCF7 ER-positive cells led to reduced ER expression and reduced sensitivity to tamoxifen and estrogen treatment and was associated with enhanced survival and anchorageindependent growth. Finally, cDNA array analyses of murine normal mammary epithelial cells and mammary tumors identified 163 significantly downreguated and 129 upregulated genes in the tumors. The majority of differentially expressed genes were part of pathways involved in cellular movement, cell-to-cell signaling and interaction, cellular development, cellular growth and proliferation and cell death. These changes in gene expression of mouse mammary tumors in Wwox C3H þ /À mice resemble, at least in part, human breast cancer development. Our findings demonstrate the critical role that the WWOX tumor suppressor gene has in preventing tumorigenesis in breast cancer.

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Frequent loss of WWOX expression in breast cancer: correlation with estrogen receptor status

Cited by 90 publications

References 11 publications

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

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

WWOX protein expression in normal human tissues

Wwox inactivation enhances mammary tumorigenesis

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