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Nuclear localization of Kaiso promotes the poorly differentiated phenotype and EMT in infiltrating ductal carcinomas.

ABSTRACT: The expression and biological consequences of Kaiso, a novel bi-modal transcription factor, in infiltrating ductal carcinomas (IDCs) have not been widely investigated. In the present study, we determined Kaiso expression and subcellular localization in 146 normal tissues, 376 IDCs, and 85 lymph node metastases. In IDCs, there was higher Kaiso expression in both the cytoplasmic and nuclear compartments, which correlated with age <48 (cytoplasmic p < 0.0093; nuclear p < 0.0001) and moderate differentiation (cytoplasmic p < 0.0042; nuclear p < 0.0001), as determined by Chi square analysis. However, only nuclear Kaiso correlated with poor prognostic factors, i.e., race (African Americans) (p < 0.0001), poor differentiation (p < 0.0001), and metastases (p < 0.0001). Nuclear Kaiso was also associated with worse overall survival (p < 0.0019), with African American patients displaying worse survival rates relative to Caucasian patients (p < 0.029). MCF-7 (non-metastatic), MDA-MB-468 (few metastases), and MDA-MB-231 (highly metastatic) breast cancer cells demonstrated increasing Kaiso levels, with more nuclear localization in the highly metastatic cell line. Over-expression of Kaiso in MCF-7 cells increased cell migration and invasion, but treatment of MDA-MB-468 and MDA-MB-231 cells with si-Kaiso decreased cell migration and invasion and induced expression of E-cadherin RNA and protein. E-cadherin re-expression was associated with a reversal of mesenchymal associated cadherins, N-cadherin and cadherin 11, as well as decreased vitamin expression. Further, Kaiso directly bound to methylated sequences in the E-cadherin promoter, an effect prevented by 5-aza-2-deoxycytidine. Immunofluorescence co-staining of poorly differentiated IDCs demonstrated that nuclear Kaiso is associated with a loss of E-cadherin expression. These findings support a role for Kaiso in promoting aggressive breast tumors.

SUBMITTER: Jones J

PROVIDER: S-EPMC4065802 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Nuclear localization of Kaiso promotes the poorly differentiated phenotype and EMT in infiltrating ductal carcinomas.

Jones Jacqueline J Wang Honghe H Karanam Balasubramanyam B Theodore Shaniece S Dean-Colomb Windy W Welch Danny R DR Grizzle William W Yates Clayton C

Clinical & experimental metastasis 20140226 5

The expression and biological consequences of Kaiso, a novel bi-modal transcription factor, in infiltrating ductal carcinomas (IDCs) have not been widely investigated. In the present study, we determined Kaiso expression and subcellular localization in 146 normal tissues, 376 IDCs, and 85 lymph node metastases. In IDCs, there was higher Kaiso expression in both the cytoplasmic and nuclear compartments, which correlated with age <48 (cytoplasmic p < 0.0093; nuclear p < 0.0001) and moderate differ ...[more]

PMID: 24570268

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Project description:Introduction: A major challenge in the interpretation of genomic profiling data generated from breast cancer samples is the identification of driver genes as distinct from bystander genes which do not impact tumorigenesis. One way to assess the relative importance of alterations in the transcriptome profile is to combine complementary analyses that assess changes in the copy number alterations (CNAs). This integrated analysis permits the identification of genes with altered expression that map within specific chromosomal regions that demonstrate copy number alterations, providing a mechanistic approach to identify the 'driver genes’. Methods: We have performed whole genome analysis of CNAs using the Affymetrix 250K Mapping array on 22 infiltrating ductal carcinoma samples (IDCs). Analysis of transcript expression alterations was performed using the Affymetrix U133 Plus2.0 array on 16 IDC samples. Twelve IDC samples were analyzed using both platforms and the data integrated. We also incorporated data from LOH analysis to identify genes showing loss of expression in LOH regions. Results: Copy number analysis results demarcated smaller boundaries for many previously reported CNAs, and in some cases, the CNAs were defined as more than a single contiguous event. Additionally, we were able to assign driver genes to these commonly reported regions using a rigorous methodology. For example, RAB25 showed a large increased expression in the tumors and mapped to the commonly reported amplification at 1q22. We also identified 5 genes in the 8q24 amplicon and TSEN4 in the 17q25 amplified region. LOH analysis confirmed some previously reported regions, and integration with copy number data determined that the detected LOH were copy neutral events. Finally, we have identified several RXR pathways that demonstrated down-regulation in IDC whose members may represent further targets of therapeutic intervention. Conclusion: We have demonstrated the utility of the application of integrated analysis using high-resolution CGH and whole genome transcript analysis for detecting driver genes in IDC. The high resolution platform allowed a refined demarcation of CNAs, and gene expression profiling provided a mechanism to detect genes directly impacted by the CNA. This is the first report of LOH in IDC using a high resolution platform. 16 IDC samples analyzed with the U133 Plus 2.0 array compared to 4 normal control samples.

Project description:BACKGROUND:Extrapulmonary neuroendocrine carcinomas (NECs) are poorly studied and are managed similar to lung NECs, which may not account for differences between the 2 groups of tumors as well as the heterogeneity within extrapulmonary NEC. METHODS:Data from the Surveillance, Epidemiology, and End Results program between 1973 and 2012 were used to estimate the relative percentages of lung NECs and subgroups of extrapulmonary NECs, epidemiological patterns at these sites, and the median and 5-year overall survival rates. RESULTS:Of 162,983 NEC cases, 14,732 were extrapulmonary; of these, 5509 were gastrointestinal (37.44%), 4151 were of unknown primary (28.2%), and 5072 were of other sites (34.4%). Lung NEC had the highest percentage of small cell morphology (95.2%) and gastrointestinal NEC had the least (38.7%), with the rest being other morphologies. Significant differences were noted with regard to median age (range, 48-74 years), percentage of cases of distant stage disease (24%-77%), and incidence according to sex and race. The median survival of patients with lung NEC was 7.6 months, that for patients with gastrointestinal NEC was 7.5 months (range, 25.1 months for NEC at the small intestine to 5.7 months for NEC at the pancreas), and that for patients with unknown NEC was 2.5 months. The 5-year survival rate for patients with local stage disease ranged from 58% to 60% for NECs of the female genital tract and small intestine to 25% for esophageal NECs. The primary tumor site remained statistically significant for survival even after adjusting for known prognostic variables (P<.0001). CONCLUSIONS:To the authors' knowledge, the current study is the largest study of NECs performed to date and also the first with comprehensive epidemiological data. Significant differences in incidence patterns and large variations in survival depending on anatomical site and morphological subtype were noted. A curative approach is possible for patients with nonmetastatic NECs. Cancer 2018;124:807-15. © 2017 American Cancer Society.

Dataset Information

Nuclear localization of Kaiso promotes the poorly differentiated phenotype and EMT in infiltrating ductal carcinomas.

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Nuclear localization of Kaiso promotes the poorly differentiated phenotype and EMT in infiltrating ductal carcinomas.

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