Systematic identification and molecular characterization of genes differentially expressed in breast and ovarian cancer

Dahl, Edgar; Sadr‐Nabavi, Ariane; Klopocki, Eva; Betz, Beate; Grube, Susanne; Kreutzfeld, Rene; Himmelfarb, Marina; An, Han‐Xiang; Gelling, S.; Klaman, Irina; Hinzmann, Bernd; Kristiansen, Glen; Grützmann, Robert; Kuner, Ruprecht; Petschke, Beate; Rhiem, Kerstin; Wiechen, Kai; Sers, Christine; Wiestler, Otmar D.; Schneider, Achim; Höfler, Heinz; Nährig, Jörg; Dietel, Manfred; Schäfer, Reinhold; Rosenthal, André; Schmutzler, Rita; Dürst, Matthias; Meindl, Alfons; Niederacher, Dieter

doi:10.1002/path.1687

Cited by 52 publications

(53 citation statements)

References 25 publications

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“…It has further been shown that malfunctions in nuclearcytoplasmic shuttling may contribute to carcinogenesis, for example, of breast and colon (Flamini et al, 1996;Lu et al, 2000). Therefore, the objective of this study was to unveil the potential phenotypical consequences of KPNA2 overexpression in vitro, as frequently found in breast cancer patients ex vivo (Dahl et al, 2005). As a prerequisite for such in depth functional characterization, gain-of-function models capable of overexpressing KPNA2 were required.…”

Section: Discussionmentioning

confidence: 99%

“…We previously discovered overexpression of KPNA2 mRNA in invasive breast cancer (Dahl et al, 2005), and subsequently demonstrated that breast cancer patients with increased nuclear KPNA2 protein expression in tumor cells presented advanced tumor size, poor tumor differentiation, reduced overall and recurrence-free survival (Dahl et al, 2006). Further gene expression studies revealed aberrant KPNA2 expression in premalignant and non-invasive ductal carcinomas in situ, indicating that this event occurs already in early stages of breast cancer development (Dankof et al, 2007;Klein et al, 2007).…”

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confidence: 97%

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Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

et al. 2011

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Tumorigenesis and tumor progression are associated with dysfunction of the nuclear transport machinery at the level of import and export receptors (karyopherins). Recent studies have shown that the nuclear import factor karyopherin-a2 (KPNA2) is a novel prognostic marker for poor prognosis in human breast cancer. Based on the well-defined hallmarks of cancer progression, we performed a detailed in vitro characterization of the phenotypic effects caused by KPNA2 overexpression and KPNA2 silencing in benign and malignant human breast cells. KPNA2 overexpression clearly increased proliferation of MCF7 tumor cells and further led to a reduction of cell-matrix adhesion in benign MCF10A cells, whereas cell migration was significantly increased (Po0.0001) in both tumor models. Remarkably, these individual effects of KPNA2 overexpression on proliferation, cell-matrix adhesion and migration resulted in an increased colony spreading of benign MCF10A breast cells and malignant MCF7 tumor cells (Po0.001), which is a hallmark of cancer progression. Conversely, RNA interference-mediated KPNA2 silencing caused a complete inhibition of MCF7 tumor cell proliferation and migration (Po0.0001). In addition, in these experiments apoptosis was increased (Po0.05) and formation of tumor cell colonies was reduced (Po0.01). Thus, KPNA2 overexpression provoked increased aggressiveness of malignant MCF7 breast tumor cells and induced a shift in benign MCF10A breast cells toward a malignant breast cancer phenotype. In conclusion, we demonstrate for the first time in experimental tumor models that forced KPNA2 expression drives malignant features relevant for breast cancer progression, while its silencing is required for the remission of those progressive phenotypes. This study gives clear evidence that KPNA2 acts as a novel oncogenic factor in human breast cancer, in vitro.

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Section: Discussionmentioning

confidence: 99%

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confidence: 97%

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

et al. 2011

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“…A clinical study of pancreatic ductal adenocarcinomas previously showed that high CapG expression was correlated with increased tumor size (Thompson et al, 2007a,b). Some researchers have reported that RNAi knockdown of CapG in human cancer cells, such as breast and pancreatic cancer cells can significantly reduce the invasion and motility of cancer cells and cell aggression (Dahl et al, 2005;Thompson et al, 2007a,b;Kang et al, 2010;Xu et al, 2010). CapG is considered to be a tumor promoter and can modulate invasive properties of cells during tumorigenesis (Veerle et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Evaluation of CapG, Gelsolin, P‐gp, GSTP1, and Topo‐II Proteins in Non‐Small Cell Lung Cancer

Zhu

Hunag

Liu

et al. 2011

The Anatomical Record

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Metastasis and multidrug resistance (MDR) are the main reasons for the poor prognosis of non-small cell lung cancer (NSCLC) patients. The use of biomarkers may contribute to a more accurate prediction of tumor metastasis, a better response to chemotherapy, and better patient survival. Gelsolin-like actin-capping protein (CapG) and gelsolin have been identified as playing important roles in tumor invasion and metastasis. Permeability glycoprotein (P-gp), glutathione S-transferase pi (GSTP1), and topoisomerase-II (Topo-II) are proteins that are closely related to MDR. In this study, we assessed the prognostic significance of CapG and gelsolin (both markers of tumor motility), and of P-gp, GSTP1, and Topo-II (markers of MDR) in NSCLC patients. One hundred and twenty-one patients with pathologically confirmed, resectable NSCLC were included in the study. The expression levels of the five kinds of proteins mentioned above were determined by immunohistochemistry (IHC). The correlation between the clinical characteristics and IHC findings were analyzed. Expression of CapG, gelsolin, and P-gp was found to be associated with an increased risk of death (Hazard Ratio (HR) ¼ 2.799, 95% Confidence Interval (CI) ¼ 1.2705-6.169, P ¼ 0.011; HR ¼ 3.968, 95% CI ¼ 1.811-8.693, P ¼ 0.001; HR ¼ 3.251, 95% CI ¼ 1.456-7.260, P ¼ 0.004, respectively), whereas expression of GSTP1 and Topo-II was not. These results suggest that higher tumor motility and MDR may be important in NSCLC prognosis. Anat Rec, 295:208-214, 2012. V V C 2011 Wiley Periodicals, Inc.Key words: NSCLC; CapG; gelsolin; P-gp; prognosisLung cancer remains the leading cause of cancerrelated deaths in China, in both males and females. The most common form of lung cancer, non-small cell lung cancer (NSCLC), has a 5-year relative survival rate below 70% in patients with Stage I tumors, and below 1% in patients with Stage IV tumors (Jemal et al., 2009). Treatment of patients with NSCLC is governed by various prognostic factors such as surgical stage, histological grade, differentiation, and lymph node metastasis. Nevertheless, the clinical outcome in individual patients is often difficult to predict.The main cause of death from lung cancer is usually related to metastasis and resistance to chemotherapeutics after primary surgery. If prognosis could be determined more precisely before treatment, then patients would be more effectively treated with individualized therapy. Compared with mRNAs, which degrade quickly if samples are not prepared correctly, proteins are more stable and potentially very useful biomarkers. Furthermore, differences in protein expression may reveal information about biological properties of tumors.

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“…Various studies (Kobayashi et al, 1995;Bourguignon et al, 1999;Paris et al, 2002;Zhang et al, 2004) have shown involvement of ITIs in tumour biology using an expressed sequence-tag-based bioinformatics approach (Dahl et al, 2005). We have previously identified ITIH5 as a novel gene differentially expressed in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

et al. 2007

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Inter-a-trypsin inhibitors (ITIs) are protease inhibitors stabilizing the extracellular matrix. ITIs consist of one light (bikunin) and two heavy chains (ITIHs). We have recently characterized ITIH5, a novel member of the ITIH gene family, and showed that its messenger RNA is lost in a high proportion of breast tumours. In the present study, an ITIH5-specific polyclonal antibody was generated, validated with western blot and used for immunohistochemical analysis on a tissue microarray; ITIH5 was strongly expressed in epithelial cells of normal breast (n ¼ 11/15), while it was lost or strongly reduced in 42% (92/217) of invasive breast cancers. ITIH5 expression in invasive carcinomas was associated with positive expression of oestrogen receptor (P ¼ 0.008) and histological grade (P ¼ 0.024). Correlation of ITIH5 expression with clinical outcome revealed that patients with primary tumours retaining abundant ITIH5 expression had longer recurrence-free survival (RFS; P ¼ 0.037) and overall survival (OS; P ¼ 0.044), compared to those with reduced expression (mean RFS: 102 vs 78 months; mean OS: 120 vs 105 months). Methylation-specific PCR analysis frequently showed strong methylation of the ITIH5 promoter in primary breast tumours (41%, n ¼ 109) and breast cancer cell lines (n ¼ 6). Methylation was significantly associated with mRNA loss (Po0.001; n ¼ 39), and ITIH5 expression was induced after treatment of tumour cell lines with the demethylating agent 5-aza-2 0 -deoxycytidine. Moreover, ITIH5 promoter methylation was significantly associated with reduced OS (P ¼ 0.008). The cellular function of ITIH5 was evaluated by forced expression of a full-length ITIH5 complementary DNA in the breast cancer cell line MDA-MB-231, which does not endogenously express ITIH5. ITIH5-expressing clones showed a 40% reduced proliferation rate compared to mock-transfected cells. Overall, these data show that promoter methylation-mediated loss of ITIH5 expression is associated with unfavourable outcome in breast cancer patients, and thus ITIH5 could be used as a prognostic marker, although this marker is not multivariate independent due to its close association with ER expression. Our data indicate that ITIH5 is a candidate class II tumour suppressor gene and could be involved in tumour progression, invasion and metastasis, as its absence is associated with increased proliferation rates and a prognostic value indicating poor clinical outcome.

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Systematic identification and molecular characterization of genes differentially expressed in breast and ovarian cancer

Cited by 52 publications

References 25 publications

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

Prognostic Evaluation of CapG, Gelsolin, P‐gp, GSTP1, and Topo‐II Proteins in Non‐Small Cell Lung Cancer

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

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