Abnormal expression of Nek2 and β-catenin in breast carcinoma: Clinicopathological correlations
Department of Breast Cancer Pathology and Research Laboratory of Tianjin Medical University, China. Histopathology
(Impact Factor: 3.45).
10/2011; 59(4):631-42. DOI: 10.1111/j.1365-2559.2011.03941.x
NIMA-related kinase 2 (Nek2) and β-catenin are important centrosome regulatory factors. The aim of this study was to detect the possible disparity in their expression among normal breast tissue, invasive ductal carcinoma (IDC), concomitant ductal carcinoma in situ (DCIS), and pure DCIS, and to explore its correlation with clinicopathological factors.
We used immunohistochemistry to detect protein expression of Nek2 and β-catenin in breast cancer tissues from 60 cases of pure DCIS, 348 cases of IDC and 137 cases of concomitant DCIS with that in normal breast tissues from the same 137 concomitant DCIS patients as controls. As compared with normal tissue, expression of Nek2 and β-catenin in the cytoplasm was significantly increased in IDC and DCIS (P < 0.05), and variation in expression was also observed in different grades of IDC (P < 0.01). Also, cytoplasmic expression of Nek2 and and of β-catenin were correlated with each other in IDC and DCIS (P < 0.01). In addition, they were both related to Ki67 immunoreactivity (P < 0.05). Furthermore, our study also revealed a correlation between their expression and some clinicopathological factors. We found that Nek2 cytoplasmic expression was associated with grade and tumour size (P < 0.01) in IDC, whereas β-catenin cytomembrane expression showed significant variation with grades, TNM stages, lymphoid node status, oestrogen receptor status, and molecular subtype (P < 0.05); a difference in expression was also observed between IDC and DCIS (P < 0.05). Also, β-catenin cytoplasmic expression was associated with TNM stage (P < 0.05). Expression of Nek2 at the mRNA level was detected in 50 pairs of breast cancer specimens and matched normal tissues by reverse transcriptase polymerase chain reaction, and the result showed increased expression in IDC.
This study suggests that abnormal expression of Nek2 and β-catenin might be one of the mechanisms of tumorigenesis, especially of abnormal tumour proliferation. They may represent new potential targets for therapeutic intervention.
Available from: Swetha Raghavan
- "In our current filtering of 1q genes related to survival, CENPF (HR = 1.616; p-value = 4.90E-05) ranked first followed by NEK2 (HR = 1.641; p-value = 0.000163) which demonstrates the reliability of the strategy and the results obtained in the study. Commonality with most of the short-listed genes (CENPF, KIF14, NEK2, CKS1B and ASPM) is their positive association with proliferation marker Ki-67 [26,27,30,45,46], thereby, indicating their possible role in cell cycle related dysregulations and the resultant proliferation of breast cancer cells. However, it has been reported that simultaneous 1q gain/16q loss was related to low Ki-67 level (low proliferation) and high p27 expression of breast cancer cells . "
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ABSTRACT: Genomic aberrations are common in cancers and the long arm of chromosome 1 is known for its frequent amplifications in breast cancer. However, the key candidate genes of 1q, and their contribution in breast cancer pathogenesis remain unexplored. We have analyzed the gene expression profiles of 1635 breast tumor samples using meta-analysis based approach and identified clinically significant candidates from chromosome 1q. Seven candidate genes including exonuclease 1 (EXO1) are consistently over expressed in breast tumors, specifically in high grade and aggressive breast tumors with poor clinical outcome. We derived a EXO1 co-expression module from the mRNA profiles of breast tumors which comprises 1q candidate genes and their co-expressed genes. By integrative functional genomics investigation, we identified the involvement of EGFR, RAS, PI3K / AKT, MYC, E2F signaling in the regulation of these selected 1q genes in breast tumors and breast cancer cell lines. Expression of EXO1 module was found as indicative of elevated cell proliferation, genomic instability, activated RAS/AKT/MYC/E2F1 signaling pathways and loss of p53 activity in breast tumors. mRNA-drug connectivity analysis indicates inhibition of RAS/PI3K as a possible targeted therapeutic approach for the patients with activated EXO1 module in breast tumors. Thus, we identified seven 1q candidate genes strongly associated with the poor survival of breast cancer patients and identified the possibility of targeting them with EGFR/RAS/PI3K inhibitors.
Available from: Hans Dieter Nischalke
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ABSTRACT: It is a challenging task to distinguish between benign and malignant lesions in patients with biliary strictures. Here we analyze whether determination of target gene mRNA levels in intraductal brush cytology specimens may be used to improve the diagnosis of bile duct carcinoma.
Brush cytology specimens from 119 patients with biliary strictures (malignant: n = 72; benign: n = 47) were analyzed in a retrospective cohort study. mRNA of IGF-II mRNA-binding protein 3 (IGF2BP3), homeobox B7 (HOXB7), Forkhead box M1 (FOXM1), kinesin family member 2C (KIF2C) and serine/threonine kinase NEK2 was determined by semi-quantitative RT-PCR using the ΔCt method.
IGF2BP3 (p<0.0001), HOXB7 (p<0.0001), and NEK2 (p<0.0001) mRNA expression levels were significantly increased in patients with cholangiocarcinoma or pancreatic cancer. Median ΔCt values differed by 3.5 cycles (IGF2BP3), 2.8 cycles (HOXB7) and 1.3 cycles (NEK2) corresponding to 11-fold, 7-fold and 2.5-fold increased mRNA levels in malignant versus benign samples. Sensitivity to detect biliary cancer was 76.4% for IGF2BP3 (80.9% specificity); 72.2% for HOXB7 (78.7% specificity) and 65.3% for NEK2 (72.3% specificity), whereas routine cytology reached only 43.1% sensitivity (85.4% specificity). Diagnostic precision was further improved, when all three molecular markers were assessed in combination (77.8% sensitivity, 87.2% specificity) and achieved 87.5% sensitivity and 87.2% specificity when molecular markers were combined with routine cytology.
Our data suggest that measuring IGF2BP3, HOXB7 and NEK2 mRNA levels by RT-PCR in addition to cytology has the potential to improve detection of malignant biliary disorders from brush cytology specimens.
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ABSTRACT: Objective: To analyze the mRNA expressions of the centrosome γ-tubulin and its regulatory factor Nek2 in high/low-grade carcinoma and in atypical ductal hyperplasia and to evaluate the mechanism of breast cancer evolution. Methods: The breast tissue samples (six groups) were collected from normal tissues, atypical hyperplasia, high- and low-grade ductal carcinoma in situ, and high- and low-grade of invasive ductal carcinoma. The mRNA expression levels of γ-tubulin and Nek2 were detected by in situ hybridization in 180 samples and by real-time qRT-PCR in 80 samples. Results: The positive rate and quantity of γ-tubulin and Nek2 mRNA expressions in high/low-grade ductal carcinoma in situ and in invasive ductal carcinoma significantly increased compared with those in normal tissues (P<0.01). A significant difference was observed among the all six groups (χ2=37.519, χ2=36.912, P<0.001). The difference of mRNA expression levels between any two groups of the carcinoma was not statistically significant (P>0.05). The expressions and the abnormal up-tendencies of γ-tubulin and Nek2 mRNA were not statistically significant. Comparing the positive rate of expression between the atypical ductal hyperplasia and low-grade carcinoma, the results were χ2=1.200, 0.659, 1.148 and 2.700, respectively (P>0.05). However, the quantitative analysis of these samples showed that statistical difference between them was significant (P<0.01). Conclusion: The abnormal mRNA expression of γ-tubulin and Nek2 may have an important function in the successive proliferation of the malignant transformation process in mammary cellula epithelialis.
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