Nuclear Kaiso Expression Is Associated with High Grade and Triple-Negative Invasive Breast Cancer

Abstract

Kaiso is a BTB/POZ transcription factor that is ubiquitously expressed in multiple cell types and functions as a transcriptional repressor and activator. Little is known about Kaiso expression and localization in breast cancer. Here, we have related pathological features and molecular subtypes to Kaiso expression in 477 cases of human invasive breast cancer. Nuclear Kaiso was predominantly found in invasive ductal carcinoma (IDC) (p = 0.007), while cytoplasmic Kaiso expression was linked to invasive lobular carcinoma (ILC) (p = 0.006). Although cytoplasmic Kaiso did not correlate to clinicopathological features, we found a significant correlation between nuclear Kaiso, high histological grade (p = 0.023), ERα negativity (p = 0.001), and the HER2-driven and basal/triple-negative breast cancers (p = 0.018). Interestingly, nuclear Kaiso was also abundant in BRCA1-associated breast cancer (p<0.001) and invasive breast cancer overexpressing EGFR (p = 0.019). We observed a correlation between nuclear Kaiso and membrane-localized E-cadherin and p120-catenin (p120) (p<0.01). In contrast, cytoplasmic p120 strongly correlated with loss of E-cadherin and low nuclear Kaiso (p = 0.005). We could confirm these findings in human ILC cells and cell lines derived from conditional mouse models of ILC. Moreover, we present functional data that substantiate a mechanism whereby E-cadherin controls p120-mediated relief of Kaiso-dependent gene repression. In conclusion, our data indicate that nuclear Kaiso is common in clinically aggressive ductal breast cancer, while cytoplasmic Kaiso and a p120-mediated relief of Kaiso-dependent transcriptional repression characterize ILC.

p120-catenin in cancer – mechanisms, models and opportunities for intervention

“…Recent studies in cancer have examined localization of Kaiso in relation to p120. Overall, they indicated that nuclear Kaiso localization is decreased when p120 resides in the cytosol, although it appeared that the expression of Kaiso and its localization are highly variable, and depend on the cellular context and type of tumor examined (Soubry et al, 2005;Kantidze et al, 2009;Soubry et al, 2010;Zhang et al, 2011;Vermeulen et al, 2012). Notwithstanding this high variability, several bona fide Kaiso targets (e.g.…”

“…Another possibility is that repression of currently unknown Kaiso targets might promote tumor formation. In favor of this hypothesis is the fact that the presence of nuclear Kaiso correlates with metastatic prostate cancer and high-grade invasive ductal carcinoma (IDC), suggesting that Kaiso-mediated transcriptional repression indeed exerts oncogenic properties (Jones et al, 2012;Vermeulen et al, 2012). By contrast, non-small-cell lung cancer (NSCLC) and ILC cells show reduced levels and/or cytosolic localization of Kaiso, a p120-catenin in cancer 3519 finding that is in line with the assumption that Kaiso represses the expression of oncogenic proteins (Dai et al, 2011;Vermeulen et al, 2012).…”

Loss of p120-Catenin Induces Metastatic Progression of Breast Cancer by Inducing Anoikis Resistance and Augmenting Growth Factor Receptor Signaling

“…Analyses on human samples were conducted as described previously (28). For analysis of growth pattern and metastasis formation, Fisher exact test was used.…”

Loss of E-cadherin and epithelial to mesenchymal transition is not required for cell motility in tissues or for metastasis

“…Our results showed that in addition to stabilizing E-cadherin and b catenin, MUC1 and p120 catenin together caused significant effects on the transcription of Wnt target genes, including cyclin D1, which were distinct in the absence of either p120 catenin or MUC1. For cyclin D1, MUC1 and p120 catenin bound to and stabilized b catenin in the cell and at the cyclin D1 promoter; they also bound and caused de-repression of Kaiso, a transcriptional repressor known to be targeted by p120 catenin, 10 which together led to high levels of transcription of cyclin D1. High activity of the cyclin D1 promoter and elevated cyclin D1 protein also significantly increased cell proliferation.…”