Wwox and Ap2γ Expression Levels Predict Tamoxifen Response

Güler, Gülnur; Iliopoulos, Dimitrios; Güler, Nilüfer; Himmetoğlu, Çiğdem; Hayran, Mutlu; Huebner, Kay

doi:10.1158/1078-0432.ccr-07-1282

Cited by 62 publications

(72 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Multivariate analysis revealed AP-2γ to be an independent marker of resistance to tamoxifen, particularly in post-menopausal patients [39]. Failure of, or resistance to, anti-hormone therapy remains a major problem in the clinical management of breast cancer and several mechanisms have been proposed to account for this resistance that can equate with poor prognosis [40].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti‐hormone therapy and reduced patient survival

Gee

Eloranta²,

Ibbitt³

et al. 2008

The Journal of Pathology

View full text Add to dashboard Cite

The AP-2γ transcription factor encoded by the TFAP2C gene is a member of a family of homologous DNA binding proteins that play essential roles during vertebrate embryogenesis but show a restricted pattern of expression in the adult. Elevated expression of the AP-2α and AP-2γ family members has been associated with a number of neoplasms, particularly breast cancer. Here we present an exploratory immunohistochemical study of an archival primary breast tumour series (n = 75) with parallel clinicopathological data using a new, well-characterized antibody to AP-2γ . Heterogeneous, exclusively nuclear expression of AP-2γ was found in the epithelial and myoepithelial compartments of normal breast and within tumour epithelial cells. In the breast cancer series, the most notable association was a correlation between elevated levels of AP-2γ and shortened patient survival (p = 0.0009 * ). This relationship was also conserved in ER-positive and ErbB2-negative patients; sub-groups generally considered to have a relatively good prognosis. When patient data for survival and duration of treatment response on anti-hormone therapy were examined by multivariate analysis, AP-2γ was revealed in this study to be an independent predictor of outcome for both survival (p = 0.005) and response to anti-hormone therapy (p = 0.046). Studies using in vitro models confirmed that while tamoxifen response is associated with lower levels of AP-2γ , acquisition of resistance to this and other anti-hormone measures (eg faslodex or oestrogen deprivation) is associated with high levels of nuclear AP-2γ . Together these data suggest that elevated tumour AP-2γ expression can contribute to the failure of cells to growth arrest following anti-hormone treatment and lead to sustained growth and poorer patient outcome.

show abstract

Section: Discussionmentioning

confidence: 99%

Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti‐hormone therapy and reduced patient survival

Gee

Eloranta²,

Ibbitt³

et al. 2008

The Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…34). Some of these interactions were clinically relevant (35,36). In parallel, the Aldaz group also reported selective interaction of WWOX with PPXY-containing proteins (37) such as SMAD3 (38).…”

Section: Expanded Search: the Many Faces Of Wwox Unraveled By Its Parmentioning

confidence: 94%

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Abu-Remaileh¹,

Joy-Dodson²,

Schueler‐Furman³

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

WW domain-containing oxidoreductase (WWOX), originally marked as a likely tumor suppressor gene, has over the years become recognized for its role in a much wider range of cellular activities. Phenotypic effects displayed in animal studies, along with resolution of WWOX's architecture, fold, and binding partners, point to the protein's multifaceted biological functions. Results from a series of complementary experiments seem to indicate WWOX's involvement in metabolic regulation. More recently, clinical studies involving cases of severe encephalopathy suggest that WWOX also plays a part in controlling CNS development, further expanding our understanding of the breadth and complexity of WWOX behavior. Here we present a short overview of the various approaches taken to study this dynamic gene, emphasizing the most recent findings regarding WWOX's metabolic-and CNS-associated functions and their underlying molecular basis.The WWOX gene initially became a research target due to its localization in a region of considerable chromosomal instability (16q23.2), at common fragile site (CFS) 3 FRA16D, which immediately marked it as a possible tumor suppressor gene (TSG) (1, 2). Inactivation of TSGs at CFSs has long been known as a hallmark of cancer (3). CFSs are evolutionarily conserved genomic regions that are sensitive to replicative stress (4). In 2010, Beroukhim et al. (5) demonstrated that deletion of TSGs spanning CFSs is among the most significant driver events in cancer. Although highly recombinogenic, CFSs are rarely involved in oncogenic activation, suggesting that CFSs are mainly hot spots for inactivation of tumor suppressors (3). A number of animal studies were conducted on WWOX, and in keeping with the above paradigm, many insights were gained into WWOX's association with cancer development (reviewed elsewhere (6 -10)). However, a few surprising results led the research in other unanticipated directions, linking WWOX to regulation of metabolic function, as well as neuronal development (Fig. 1). These animal model studies were complemented by studies on the cellular and molecular levels, modeling WWOX structure and identifying its potential binding partners, thus generating a comprehensive functional model of WWOX activity.This review sketches out how our view of WWOX has evolved over the years, with emphasis on the recent findings that link WWOX to metabolic regulation and CNS homeostasis. We begin with an overview of the original WWOX animal model studies, followed by an outline of subsequent WWOX research performed at the cellular and molecular levels. We review potential WWOX binding partners and their associated cellular pathways. We further define WWOX structure and architecture, expounding its behavior in the context of its two tandem WW domains and expansive short-chain dehydrogenase/reductase (SDR) region. Taken together, we generate a functional model of WWOX that highlights the versatility of this protein and suggests possible new directions for further study of WWOX's complex nature. Animal Model...

show abstract

“…Accumulating evidence has shown that WWOX is a potential tumor suppressor. The WWOX protein interacts with p53, p73, AP-2k, YAP, erbB4, truncated c-met, and others by the WW domain in the regulation of cell growth and apoptosis [20][21][22][23][24][25][26]. The loss of WWOX has been observed in a variety of cancer cell lines and human cancers, including breast, ovarian, esophageal, lung, pancreatic, and gastric carcinomas, and is associated with the development and progression of malignant tumors [5][6][7][8][9][10][11].…”

Section: Discussionmentioning

confidence: 99%

Molecular alterations of the WWOX gene in nasopharyngeal carcinoma

Yang¹,

Hu²,

Chen³

et al. 2014

neo

View full text Add to dashboard Cite

The WW domain-containing oxidoreductase (WWOX) gene is a candidate tumor suppressor gene. However, its exact mechanism is unclear. This study aimed to investigate the role of the WWOX gene in the development of nasopharyngeal carcinoma (NPC). Tissues were collected from 65 NPC patients. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and immunohistochemistry were performed on NPC tissues to determine the expression of WWOX in NPC. The status of WWOX promoter methylation was analyzed by methylation-specific PCR. Moreover, a PCR-based loss of heterozygosity (LOH) assay was conducted to detect the presence of WWOX deletion in NPC. The expression of WWOX in NPC tissues was significantly downregulated compared with that in non-tumorous tissues (P<0.05). The low expression of WWOX was significantly correlated with clinical TNM stage (P<0.05). In addition, methylation of WWOX was detected in 27 (87%) of 31 WWOX protein negative tissues, suggesting that methylation of the WWOX promoter may regulate its expression. We found that a relatively high percentage of LOH was observed in NPC tissues. A significant inverse correlation between WWOX expression and methylation of its promoter was found in NPC tissue (rs=-0.582, P=0.001). However, LOH was not correlated with WWOX expression and methylation of its promoter. Our results show that WWOX gene alteration is an early genetic alteration and may contribute to tumorigenesis of NPC. WWOX may be an important prognostic marker in NPC.

show abstract

Wwox and Ap2γ Expression Levels Predict Tamoxifen Response

Cited by 62 publications

References 43 publications

Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti‐hormone therapy and reduced patient survival

Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti‐hormone therapy and reduced patient survival

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Molecular alterations of the WWOX gene in nasopharyngeal carcinoma

Contact Info

Product

Resources

About