Amplification/Overexpression of a Mitotic Kinase Gene in Human Bladder Cancer

Sen, Subrata; Zhou, Hongyi; Zhang, Ruo Dan; Yoon, Dong Sup; Vakar-López, Funda; Ito, Shigemi; Jiang, Feng; Johnston, Dennis A.; Grossman, H. Barton; Ruifrok, Arnout; Katz, Ruth L.; Brinkley, William R.; Czerniak, Bogdan

doi:10.1093/jnci/94.17.1320

Cited by 275 publications

(202 citation statements)

References 48 publications

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“…28 In particular, Aurora-A is a known activator of genetic pathways involving centrosome amplification and chromosomal missegregation, resulting in increased chromosome copy number and nuclear DNA content. 29 The HER2 protein is considered to have a significant role in bladder cancer outcomes, with HER2 protein expression reported in up to 31-65.5% of samples. 12,16,30 Furthermore, HER2 protein expression seems to correlate with tumor stage, tumor grade, [30][31][32] and poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

et al. 2011

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Human epidermal growth factor receptor-2 (HER2) is a well-recognized growth-promoting factor in cancer, although its application to urothelial carcinoma has been limited because of a low frequency of gene amplification. We evaluated HER2 protein expression and gene amplification in micropapillary carcinoma, a rare but highly aggressive variant of urothelial carcinoma by dual-color in situ hybridization. Gene amplification was defined by a HER2:CHR17 ratio of Z2.2; low and high levels of amplification were further defined as o2.5 and Z2.5, respectively. Immunohistochemistry was used to determine HER2 protein expression using the American Society of Clinical Oncology/College of American Pathologists Guidelines of HER2 staining. Protein expression, gene amplification, and chromosome 17 aneusomy were compared by Jonchkeere-Terpstra and Cochran-Armitage trend tests. In all, 19 of the 20 micropapillary carcinoma samples yielded usable dual-color in situ hybridization and immunohistochemistry results for evaluation. Overall, 68% (n ¼ 13) demonstrated HER2 protein expression of 2 þ to 3 þ staining. Gene amplification was present in 42% of samples (n ¼ 8), with 100% correlation with 2 þ and 3 þ protein expression. Gene amplification and protein expression were significantly associated (P ¼ 0.01). Overall, 53% of samples (n ¼ 10) had aneusomy of chromosome 17. Chromosome 17 aneusomy was present in approximately half of the samples evaluated, suggesting inherent genomic instability in this variant of urothelial carcinoma. However, increased HER2:CHR17 ratios demonstrate increased HER2 expression due to amplification in the majority of micropapillary carcinomas. These results suggest that HER2-targeted therapy may be successful on the genomic level in patients with this disease.

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Section: Discussionmentioning

confidence: 99%

HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

et al. 2011

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“…15 The tumors were grouped based on stage into noninvasive (Ta-T1a) and invasive (T1b-T4) as described previously. 16 The patient population studied consisted of 34 cases of noninvasive low-grade (grade 1-grade 2) papillary tumors, 9 cases of noninvasive highgrade (grade 3) papillary tumors, 13 cases of invasive high-grade (grade 3) papillary tumors, and 89 cases of invasive high-grade (grade 3) nonpapillary tumors. Normal urothelium from the renal pelvis and ureters from patients with no evidence of urothelial neoplasm who underwent nephrectomy were included in the microarray, and they served as control.…”

Section: Patients and Tissue Samplesmentioning

confidence: 99%

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

Inamoto

Czerniak

Dinney

et al. 2009

Cancer

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BACKGROUND:Nurr1 belongs to a novel class of orphan nuclear receptors (the NR4A family). The authors have previously shown that Nurr1 is important in carcinogenesis. In the current study, they examined the clinicopathologic relevance of expression patterns of Nurr1 in bladder tumors.METHODS:Nurr1 expression was determined using immunohistochemical staining in a bladder cancer tissue array (145 tumors). Tumors were classified according to Nurr1 protein levels in both cytoplasm and nucleus. Disease‐specific survival and recurrence‐free survival were investigated by Kaplan‐Meier analysis and Cox proportional hazards analysis in multivariate models and correlated with variables such as tumor stage, growth pattern, and clinical outcome (recurrence and survival). In vitro, Nurr1 was examined for its role in bladder cancer cell proliferation and migration using small interfering RNA silencing.RESULTS:Nurr1 expression in tumor cells correlated with increasing tumor stage and invasive growth pattern. Disease‐specific survival was significantly shorter in patients whose tumors demonstrated a high level of cytoplasmic Nurr1 compared with those with lower levels of cytoplasmic Nurr1 expression. Furthermore, cytoplasmic Nurr1 expression level was found to be an independent predictor of disease‐specific survival (odds ratio, 4.894; P < .001). In vitro, silencing of endogenous Nurr1 attenuated the migration of bladder cancer cells.CONCLUSIONS:The expression of Nurr1 in the cytoplasm correlates with adverse outcome and is an independent prognostic marker for tumor progression and survival in patients with bladder cancer. This might represent a novel target in bladder cancer therapy. Cancer 2010. © 2010 American Cancer Society.

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“…Probes were tested by FISH on interphase nuclei and metaphase spreads from normal lymphocytes and yielded two signals. One hundred interphase cell nuclei of each tumor sample were analyzed and ratios (target BAC/control) of >2 were assessed as amplification (33).…”

Section: Fishmentioning

confidence: 99%

Suppression of Anoikis by SKP2 Amplification and Overexpression Promotes Metastasis of Esophageal Squamous Cell Carcinoma

Wang

Ye³

et al. 2009

Molecular Cancer Research

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The gene of SKP2, located on chromosome 5p13, plays a critical role in cell cycle progression, especially at the G 1 -S transition, putatively through its control of several cell cycle regulator proteins including p27 kip1 , p21 cip1 , p57 kip2 , p130, cyclin E, and c-Myc. Previous studies in this laboratory revealed that gain of chromosome 5p was often seen in esophageal squamous cell carcinoma (ESCC). In the present study, we examined the amplification status and expression level of SKP2 in ESCC and investigated its clinicopathologic significance. Amplification and elevated expression of SKP2 correlated significantly with tumor stage and positive lymph node metastasis (P < 0.05). The SKP2 protein expression level as determined by immunohistochemical staining showed a significant inverse correlation with p27 protein. In vivo assay showed that inhibition of SKP2 expression also decreased tumor growth and lung metastasis of ESCC cells. At the molecular level, knockdown of SKP2 by RNA interference inhibited cell migration and invasion ability. Knockdown of SKP2 expression sensitized cancer cells to anoikis, and a wobble mutant of SKP2 that is resistant to SKP2 small interfering RNA can rescue this effect. Expression level of pAkt decreased after SKP2 knockdown. Treatment of cells with phosphoinositidyl 3-kinase inhibitor (LY294002) and constitutively activator (insulin-like growth factor I) had significant effects on the anoikis of SKP2 RNA interference cells. These results show for the first time that SKP2 is amplified and overexpressed in ESCC. Elevated expression of SKP2 protected cancer cells from anoikis, and this effect was mediated, at least in part, by the phosphoinositidyl 3-kinase-Akt pathway.

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Amplification/Overexpression of a Mitotic Kinase Gene in Human Bladder Cancer

Abstract: STK15 gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behavior in human bladder cancer.

Cited by 275 publications

References 48 publications

HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

Suppression of Anoikis by SKP2 Amplification and Overexpression Promotes Metastasis of Esophageal Squamous Cell Carcinoma

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