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

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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.

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Abbreviations

IDC:

Infiltrating ductal carcinoma

BTB-POZ:

Broad complex, tramtrak bric-a-brac/pox virus, and zinc finger subfamily of zinc-finger proteins

CDH1 :

Cadherin-1 gene

EMT:

Epithelial to mesenchymal transition

TMA:

Tissue microarray

siRNA:

Small-interfering RNA

RFP:

Red fluorescence protein

PMSF:

Phenylmethylsulfonyl fluoride

DAPI:

2,4-Diamidino-2-phenylindole

qRT-PCR:

Quantitative real-time PCR

EGFR:

Epidermal growth factor receptor

5-aza:

5-Aza-2-deoxycytidine

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Acknowledgments

This work was supported by Grants G12 RR03059-21A1 (NIH/RCMI) [CY] and a pilot project on U54 CA118948 (NIH/NCI) [CY]. Partial support was received from R01 CA87728 (NIH), Susan G. Komen for the Cure, and the National Foundation for Cancer Research [DRW]. Pre-doctoral fellowship for Jacqueline Jones was supported by UNCF/Merck graduate science initiative. We would like to thank members of the Yates Laboratory for their comments and discussions.

Conflict of interests

The authors have filed a patent application relating to the content of this manuscript but have no further conflicting financial interests

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Authors and Affiliations

  1. Department of Biology and Center for Cancer Research,Carver Research Foundation, Tuskegee University, Rm # 22, Tuskegee, AL, 36088, USA

    Jacqueline Jones, Honghe Wang, Balasubramanyam Karanam, Shaniece Theodore & Clayton Yates

  2. Department of Oncology, University of South Alabama Mitchell Cancer Center, Mobile, AL, 36688, USA

    Windy Dean-Colomb

  3. Department of Cancer Biology, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS, 66045, USA

    Danny R. Welch

  4. Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35205, USA

    William Grizzle

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  1. Jacqueline Jones
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  2. Honghe Wang
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  3. Balasubramanyam Karanam
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  8. Clayton Yates
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Correspondence to Clayton Yates.

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Jones, J., Wang, H., Karanam, B. et al. Nuclear localization of Kaiso promotes the poorly differentiated phenotype and EMT in infiltrating ductal carcinomas. Clin Exp Metastasis 31, 497–510 (2014). https://doi.org/10.1007/s10585-014-9644-7

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