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

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.

ElevatedCRB3 expression suppresses breast cancer stemness by inhibiting β‐catenin signalling to restore tamoxifen sensitivity

“…However, tamoxifen resistance has become a roadblock for successful treatment and caused the failure of tamoxifen‐related therapy. Our previous study found that decreased CRB3 expression led to the acquirement of cancer stem cell‐like properties in non‐tumorigenic, immortalized breast epithelial cell line MCF 10A . Thus, the current study has been suggested that increased expression of cell polarity protein CRB3 might inhibit stemness characteristics of breast cancer that in turn overcomes tamoxifen resistance.…”

Crumbs protein homolog 3 (CRB3) expression is associated with oestrogen and progesterone receptor positivity in breast cancer

“…In the current study, we found that CRB3 expression was inversely associated with tumour size (Table ), which is consistent with previous studies showing that downregulation of CRB3 expression induced breast cancer cell proliferation, whereas CRB3 overexpression inhibited proliferation of human breast cell lines . Our previous study also showed that the downregulation of CRB3 expression increased migration and invasion of breast cancer cells, whereas CRB3 overexpression inhibited migration and invasion of human breast and kidney cancer cell lines .…”

“…Our previous study revealed that CRB3 expression was lower in breast cancer compared with that of normal mammary gland tissues. 20 In this study, we detected CRB3 expression in 192 invasive human breast cancers (Table 1) immunohistochemically. The data showed that CRB3 protein was expressed in 65/192 (33.8%) cases of the cytoplasm of tumour cells ( Figure 1).…”

“…20,45,46 Our previous study also showed that the downregulation of CRB3 expression increased migration and invasion of breast cancer cells, whereas CRB3 overexpression inhibited migration and invasion of human breast and kidney cancer cell lines. 20,47 Our previous study also showed that CRB3 expression was an independent favourable predictor for renal clear cell carcinoma. 47 In summary, our current study is a proof-of-principle.…”

“…In our current study, we sought to identify novel targets for the future control of TNBC and found that CRB3 expression was significantly lost in TNBC tissues and cell lines, but the molecular events responsible for loss of CRB3 expression in human breast tumours remain to be determined. Our previous study revealed that CRB3 expression was lower in breast cancer compared with that of normal mammary gland tissues, while Varelas et al reported that disruption of the CRB complex predisposed TGF‐β‐mediated mouse mammary epithelial epithelial‐mesenchymal transition.…”