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 vitmenin 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.

Inhibition of the Warburg effect with a natural compound reveals a novel measurement for determining the metastatic potential of breast cancers

“…This suggests the possibility that PP, via modulation of NF-κB, is involved in demethylation of the LDH-B promoter. This premise is supported by our previous work showing that PP treatment results in increased expression of E-cadherin, the promoter of which is hypermethylated in MDA-MB-231 breast cancer cells [22, 32]. …”

African Americans with pancreatic ductal adenocarcinoma exhibit gender differences in Kaiso expression

“…Kaiso, a bimodal transcription factor, belonging to the BTB/POZ (Broad Complex, Tramtrak, Bric à brac/Pox virus and Zinc finger) subfamily of zinc-finger proteins, binds both methylated DNA and consensus Kaiso binding s ites (KBS) on DNA to regulate gene expression [6–8]. A function of Kaiso in tumorigenesis is methylation-dependent silencing of various tumor suppressor genes.…”

“…A function of Kaiso in tumorigenesis is methylation-dependent silencing of various tumor suppressor genes. For example, in prostate and breast cancers, Kaiso regulates genes that relate to de-differentiation, including those associated with the epithelial–mesenchymal transition (EMT), such as E-cadherin [8,9], Wnt 11 [10], and matrilysin [11]. Additionally, in MCF-7 breast cancer cells, Kaiso regulates the cyclin D1 promoter via binding to methylated CpG-dinucleotides and KBS [12].…”

“…In more aggressive tumors, Kaiso shows a trend of increased nuclear expression [12,18]. In prostate cancer cells, nuclear Kaiso silences E-cadherin and induces these cells to undergo an EMT [8,9]. Also, depletion of Kaiso in breast cancer cell lines causes a reduction in the EMT markers, N-cadherin and vimentin [8].…”

“…In prostate cancer cells, nuclear Kaiso silences E-cadherin and induces these cells to undergo an EMT [8,9]. Also, depletion of Kaiso in breast cancer cell lines causes a reduction in the EMT markers, N-cadherin and vimentin [8]. Nuclear Kaiso is elevated in prostate and breast tumors of African American patients, who typically have highly aggressive tumors of these types [8,9].…”