CRB3 downregulation confers breast cancer stem cell traits through TAZ/\u03b2-catenin

P Li,Y Jiang,R Wang,P Liu,Y Wang,J She,J Zhang,J Liu,X Mao,Y Liu,J Li,J Yang,J Wang

doi:10.1038/oncsis.2017.24

Abstract

The cancer stem cell (CSC) theory depicts a special population within the cancer mass that self-renew and sustain the cancer, even if the other cells were eliminated by therapies. How CSCs acquire these unique traits is still unclear. Crumbs homolog 3 (CRB3), a member of the CRB polarity complex, has been reported to act as a tumor suppressor. Here, we detected significantly lower or negative CRB3 expression in human breast cancer tissues. Knockdown of CRB3 generated non-tumorigenic, immortalized breast epithelial cell line MCF 10A with CSC properties. Simultaneously, we found that CRB3 downregulation induced the epithelial–mesenchymal transition and activated TAZ (transcriptional co-activator with PDZ-binding motif) and β-catenin. Significantly, the activation of TAZ and β-catenin sufficed in conferring MCF 10A cells with CSC properties. This study demonstrates that cell polarity proteins may serve as a switch of the differentiated vs multipotent states in breast cancers.

Highlights

The dysregulation of cell polarity proteins plays an important role in cancer development
We found that Crumbs homolog 3 (CRB3) was strongly expressed in normal breast epithelial tissues, but weakly expressed in breast cancer tissues
These data suggest that CRB3 may be a cancer suppressor, which is consistent with Karp and his colleagues’ previous findings that CRB3 expression correlates inversely with migration and invasion of the mouse kidney epithelial cells and that reduced expression of CRB3 can promote carcinogenesis of murine kidney epithelia.[7]

Summary

Introduction

The dysregulation of cell polarity proteins plays an important role in cancer development. The establishment and maintenance of epithelial polarity primarily depends on three cell polarity complexes, namely the Crumbs (CRB) complex, the partitioning defective (PAR) complex and the Scribble (SCRIB) complex.[1]. Of all the human Crumbs isoforms, only CRB3, one of the three human Crumbs isoforms (CRB1–3) that is localized to the apical membrane, is widely expressed in the epithelium.[2,3] Whiteman et al. Found that CRB3 was essential for proper epithelial development and viability. CRB3 knockout mice died shortly after birth and displayed epithelial morphogenesis defects such as cystic kidneys, proteinaceous debris throughout the lungs, villus fusion and apical membrane blebs in the intestines.[4] CRB3 repression disrupted tight junction (TJ) formation, while CRB3 increased the expression of the TJ proteins occludin and ZO-1.5–11

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Conclusion