Fragile histidine triad protein, WW domain‐containing oxidoreductase protein Wwox, and activator protein 2γ expression levels correlate with basal phenotype in breast cancer

Güler, Gülnur; Huebner, Kay; Himmetoğlu, Çiğdem; Jimenez, Rafael E.; Costinean, Stefan; Volinia, Stefano; Pilarski, Robert; Hayran, Mutlu; Shapiro, Charles L.

doi:10.1002/cncr.24103

Cited by 41 publications

(38 citation statements)

References 37 publications

(114 reference statements)

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“…In univariate analysis, WWOX loss was more frequent in ER and PR negative basal-like tumors (Table 2). These data suggest that characteristics of mammary tumors in Wwox C3H þ /À mice resemble those of human breast cancers where WWOX loss is associated with triple negative basal-like (CK5/6) breast cancers (Guler et al, 2009). This group, accounting for 15% of all breast cancers, is often characterized by BRCA1 mutations.…”

Section: Frequent Loss Of Wwox Er and Pr In Mammary Tumors Frommentioning

confidence: 75%

“…All of the female heterozygous mice that developed mammary abnormalities developed ductal carcinoma in situ ( Figure 1A- (Kurek et al, 2010). Polyclonal anti-WWOX antibody (Guler et al, 2009) at a dilution of 1:10 000 was used. Tumors were grouped into three categories (positive, reduced, negative) based on the intensity of cytoplasmic staining in all tumor cells present on the slides.…”

Section: Resultsmentioning

confidence: 99%

“…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)). Loss of heterozygosity and hypermethylation affecting WWOX have been reported as main causes of WWOX alterations in breast tumors (Bednarek et al, 2000;Iliopoulos et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Frequent Loss Of Wwox Er and Pr In Mammary Tumors Frommentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Wwox inactivation enhances mammary tumorigenesis

et al. 2011

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“…10,47 Tyr33-phosphorylated WWOX binds to the 47 In basal-like breast cancer cells, elevated nuclear AP2g expression may be partially due to the reduced WWOX expression, indicating that the formation of WWOX-AP2g complexes is involved in the regulation of basal-like breast cancer development. 48 UV irradiation induces phosphorylation of Wwox at Tyr33 in hairless mouse epidermis. 36 Following exposure to UV irradiation, WWOX interacts with the PPVY motif of phosphorylated c-Jun and attenuates MEKK1-stimulated binding of c-Jun to an AP-1 element in human HaCaT keratinocytes (Figure 2).…”

Section: Wwox Functions As a Tumor Suppressormentioning

confidence: 98%

Regulation of cell signaling and apoptosis by tumor suppressor WWOX

Chou

Lai

et al. 2015

Exp Biol Med (Maywood)

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Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (named WWOX, FOR, or WOX1). Functional suppression of WWOX prevents apoptotic cell death induced by a variety of stress stimuli, such as tumor necrosis factor, UV radiation, and chemotherapeutic drug treatment. Loss of WWOX gene expression due to gene deletions, loss of heterozygosity, chromosomal translocations, or epigenetic silencing is frequently observed in human malignant cancer cells. Acquisition of chemoresistance in squamous cell carcinoma, osteosarcoma, and breast cancer cells is associated with WWOX deficiency. WWOX protein physically interacts with many signaling molecules and exerts its regulatory effects on gene transcription and protein stability and subcellular localization to control cell survival, proliferation, differentiation, autophagy, and metabolism. In this review, we provide an overview of the recent advances in understanding the molecular mechanisms by which WWOX regulates cellular functions and stress responses. A potential scenario is that activation of WWOX by anticancer drugs is needed to overcome chemoresistance and trigger cancer cell death, suggesting that WWOX can be regarded as a prognostic marker and a candidate molecule for targeted cancer therapies.

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“…Given the differential frequency of FRA3B activation in epithelial cells versus fibroblasts, these findings suggest that FHIT protein loss, whether through FRA3B fragility or other mechanisms, could be associated with activation of other CFSs such as the FRA16D locus harboring the WWOX gene. Investigators have documented, over many years, the combined loss of FHIT and WWOX, particularly for breast cancer, including familial breast cancers [Masson et al, 2014], sporadic breast cancers [Guler et al, 2005;Pluciennik et al, 2005], and triple negative breast cancers [Guler et al, 2009[Guler et al, , 2011. Coordinate loss of FHIT and WWOX in breast cancer has been established through immunohistochemistry of breast tumor and normal matched tissues [Guler et al, 2009[Guler et al, , 2011 and CNV analysis of familial breast cancer patients [Masson et al, 2014], implying a possible cooperative role for loss of FHIT and WWOX in clonal expansion.…”

Section: Fhit and Wwox Gene Products At Fra3b And Fra16d Are Frequentmentioning

confidence: 99%

Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers

Karras¹,

Schrock²,

Batar³

et al. 2016

Cytogenet Genome Res

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FHIT, located at FRA3B, is one of the most commonly deleted genes in human cancers, and loss of FHIT protein is one of the earliest events in cancer initiation. However, location of FHIT at a chromosomal fragile site, a locus prone to breakage and gap formation under even mild replication stress, has encouraged claims that FHIT loss is a passenger event in cancers. We summarize accumulated evidence that FHIT protein functions as a genome “caretaker” required to protect the stability of genomes of normal cells of most tissues from agents causing intrinsic and extrinsic DNA damage. FHIT loss leads to intracellular replication stress and subsequent genome instability, which provides an opportunistic mutational landscape in preneoplasias for selection of a variety of other cancer-driving mutations. We also review evidence showing that FHIT loss leads to enhanced activation of other common fragile sites, including the FRA16D/WWOX locus, and creates optimal single-stranded DNA substrates for the hypermutator enzyme, APOBEC3B.

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Fragile histidine triad protein, WW domain‐containing oxidoreductase protein Wwox, and activator protein 2γ expression levels correlate with basal phenotype in breast cancer

Cited by 41 publications

References 37 publications

Wwox inactivation enhances mammary tumorigenesis

Wwox inactivation enhances mammary tumorigenesis

Regulation of cell signaling and apoptosis by tumor suppressor WWOX

Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers

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