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An extensive tumor array analysis supports tumor suppressive role for nucleophosmin in breast cancer.

ABSTRACT: Nucleophosmin (NPM) is a multifunctional protein involved in a complex network of interactions. The role of NPM in oncogenesis is controversial. The NPM gene (NPM1) is mutated or rearranged in a number of hematological disorders, but such changes have not been detected in solid cancers. However, experiments with cultured NPM-null cells and with mice carrying a single inactivated NPM allele indicate a tumor suppressor function for NPM. To resolve the role of NPM in solid cancers, we examined its expression and localization in histologically normal breast tissue and a large array of human breast carcinoma samples (n = 1160), and also evaluated its association with clinicopathological variables and patient survival. The intensity and localization (nucleolar, nuclear, cytoplasmic) of NPM varied across clinical samples. No mutations explaining the differences were found, but the present findings indicate that expression levels of NPM affected its localization. Our study also revealed a novel granular staining pattern for NPM, which was an independent prognostic factor of poor prognosis. In addition, reduced levels of NPM protein were associated with poor prognosis. Furthermore, luminal epithelial cells of histologically normal breast displayed high levels of NPM and overexpression of NPM in the invasive MDA-MB-231 cells abrogated their growth in soft agar. These results support a tumor suppressive role for NPM in breast cancer.

SUBMITTER: Karhemo PR

PROVIDER: S-EPMC3157231 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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An extensive tumor array analysis supports tumor suppressive role for nucleophosmin in breast cancer.

Karhemo Piia-Riitta PR Rivinoja Antti A Lundin Johan J Hyvönen Maija M Chernenko Anastasiya A Lammi Johanna J Sihto Harri H Lundin Mikael M Heikkilä Päivi P Joensuu Heikki H Bono Petri P Laakkonen Pirjo P

The American journal of pathology 20110602 2

Nucleophosmin (NPM) is a multifunctional protein involved in a complex network of interactions. The role of NPM in oncogenesis is controversial. The NPM gene (NPM1) is mutated or rearranged in a number of hematological disorders, but such changes have not been detected in solid cancers. However, experiments with cultured NPM-null cells and with mice carrying a single inactivated NPM allele indicate a tumor suppressor function for NPM. To resolve the role of NPM in solid cancers, we examined its ...[more]

PMID: 21689627

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Project description:BACKGROUND: High frequency of loss of heterozygosity (LOH) was found at D7S486 in primary gastric cancer (GC). And we found a high frequency of LOH region on 7q31 in primary GC from China, and identified D7S486 to be the most frequent LOH locus. This study was aimed to determine what genes were affected by the LOH and served as tumor suppressor genes (TSGs) in this region. Here, a high-throughput single nucleotide polymorphisms (SNPs) microarray fabricated in-house was used to analyze the LOH status around D7S486 on 7q31 in 75 patients with primary GC. Western blot, immunohistochemistry, and RT-PCR were used to assess the protein and mRNA expression of TESTIN (TES) in 50 and 140 primary GC samples, respectively. MTS assay was used to investigate the effect of TES overexpression on the proliferation of GC cell lines. Mutation and methylation analysis were performed to explore possible mechanisms of TES inactivation in GC. RESULTS: LOH analysis discovered five candidate genes (ST7, FOXP2, MDFIC, TES and CAV1) whose frequencies of LOH were higher than 30%. However, only TES showed the potential to be a TSG associated with GC. Among 140 pairs of GC samples, decreased TES mRNA level was found in 96 (68.6%) tumor tissues when compared with matched non-tumor tissues (p < 0.001). Also, reduced TES protein level was detected in 36 (72.0%) of all 50 tumor tissues by Western blot (p = 0.001). In addition, immunohistochemical staining result was in agreement with that of RT-PCR and Western blot. Down regulation of TES was shown to be correlated with tumor differentiation (p = 0.035) and prognosis (p = 0.035, log-rank test). Its overexpression inhibited the growth of three GC cell lines. Hypermethylation of TES promoter was a frequent event in primary GC and GC cell lines. However, no specific gene mutation was observed in the coding region of the TES gene. CONCLUSIONS: Collectively, all results support the role of TES as a TSG in gastric carcinogenesis and that TES is inactivated primarily by LOH and CpG island methylation.

Project description:BackgroundNischarin (encoded by NISCH), an ?5 integrin-binding protein, has been identified as a regulator of breast cancer cell invasion. We hypothesized that it might be a tumor suppressor and were interested in its regulation.MethodsWe examined nischarin expression in approximately 300 human breast cancer and normal tissues using quantitative polymerase chain reaction and immunohistochemistry. Loss of heterozygosity analysis was performed by examining three microsatellite markers located near the NISCH locus in normal and tumor tissues. We generated derivatives of MDA-MB-231 human metastatic breast cancer cells that overexpressed nischarin and measured tumor growth from these cells as xenografts in mice; metastasis by these cells after tail vein injection; and ?5 integrin expression, Rac, and focal adhesion kinase (FAK) signaling using western blotting. We also generated clones of MCF-7 human breast cancer cells in which nischarin expression was silenced and measured tumor growth in mouse xenograft models (n = 5 for all mouse experiments). P values were from two-sided Student t tests in pairwise comparisons.ResultsNormal human breast tissue samples had statistically significantly higher expression of nischarin mRNA compared with tumor tissue samples (mean level in normal breast = 50.7 [arbitrary units], in breast tumor = 16.49 [arbitrary units], difference = 34.21, 95% confidence interval [CI] = 11.63 to 56.79, P = .003), and loss of heterozygosity was associated with loss of nischarin expression. MDA-MB-231 cells in which nischarin was overexpressed had statistically significantly reduced tumor growth and metastasis compared with parental MDA-MB-231 cells (mean volume at day 40, control vs nischarin-expressing tumors, 1977 vs 42.27 mm(3), difference = 1935 mm(3), 95% CI = 395 to 3475 mm(3), P = .025). Moreover, MCF-7 tumor xenografts in which nischarin expression was silenced grew statistically significantly faster than parental cells (mean volume at day 63, tumors with scrambled short hairpin RNA [shRNA] vs with nischarin shRNA, 224 vs 1262 mm(3), difference = 1038 mm(3), 95% CI = 899.6 to 1176 mm(3), P < .001). Overexpression of nischarin was associated with decreased ?5 integrin expression, FAK phosphorylation, and Rac activation.ConclusionNischarin may be a novel tumor suppressor that limits breast cancer progression by regulating ?5 integrin expression and subsequently ?5 integrin-, FAK-, and Rac-mediated signaling.

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An extensive tumor array analysis supports tumor suppressive role for nucleophosmin in breast cancer.

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An extensive tumor array analysis supports tumor suppressive role for nucleophosmin in breast cancer.

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