Frequent inactivation of MCC/CTNNBIP1 and overexpression of phospho-beta-catenin Y654 are associated with breast carcinoma: Clinical and prognostic significance

Abstract

Transcriptional activation of β-catenin is a hallmark of Wnt/β-catenin pathway activation. The MCC (Mutated in colorectal cancers) and CTNNBIP1 (catenin, beta interacting protein 1) are two candidate genes which inhibit the transcriptional activity of nuclear β-catenin. The importance of MCC and CTNNBIP1 in breast cancer (BC) development has not yet been studied in detail. For this reason, in present study, the alterations (deletion/methylation/mutation/expression) of MCC and CTNNBIP1 were analyzed in BC of Indian patients (N=120) followed by expression/mutation analysis of β-catenin. Then transcriptional activity of β-catenin was checked by expression analysis of its target genes (EGFR, C-MYC and CCND1) in the same set of samples. Frequent methylation (44-45%) than deletion (20-32%) with overall alterations of 52-55% was observed in MCC/CTNNBIP1 in the BC samples. The alterations of MCC/CTNNBIP1 showed significant correlation with increased nuclear β-catenin/p-β-catenin(Y654) expression. Also, a significant correlation was seen between nuclear β-catenin expression and overexpression of its target genes like EGFR, MYC and CCND1 in the BC samples (P<0.0001). An upregulation of MCC and CTNNBIP1 expression by 5-Aza-2'-deoxycytidine treatment of MCF7 and MDA-MB-231 cell lines lead to downregulation of β-catenin and its target genes. The expression of nuclear p-β-catenin(Y654), EGFR, MYC and CCND1 were significantly high in TNBC (Triple negative BC) and Her2+ compared to Luminal A/B+ subtypes. The TNBC patients in stage III/IV having reduced expression of MCC in the tumors showed poor prognosis. Thus, our data suggests that inactivation of MCC/CTNNBIP1 could be an important event in activation of β-catenin mediated transcription of target genes in BC.

Ibuprofen reduces cell proliferation through inhibiting Wnt/β catenin signaling pathway in gastric cancer stem cells

“…Also, we showed that ibuprofen promoted the expression level of CTNNBIP1 in treated GCSCs. Our finding is in agreement with the one which treats MCF7 and MDA‐MB‐231 cell lines of breast cancer by 5‐Aza‐2′‐deoxycytidine to downregulate β‐catenin and its target genes by CTNNBIP1 expression (Mukherjee et al, ).…”

“…CTNNBIP1 (catenin, beta interacting protein 1) blocks the β‐catenin‐TCF interaction, so negatively regulates Wnt signaling (Mukherjee et al, ; Peng et al, ). Also, we showed that ibuprofen promoted the expression level of CTNNBIP1 in treated GCSCs.…”

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

“…Tcf7l2 transcript was earlier reported to be highly downregulated in breast cancers relative to normal breast tissue, contributing to the activation of Wnt signaling pathway (51). Furthermore, Chd8 and Mcc, negative regulators of Wnt/β-catenin pathway (52,53), were also found deleted in these tumors (Supplementary Table 1, available at Carcinogenesis Online). The data taken together indicates that aberrant expressions of PI3K/AKT and Wnt/β-catenin signaling pathways involving the copy number-altered genes play roles in Aurora-A-driven mammary tumorigenesis.…”

Integrated analysis of long noncoding RNA‐associated competing endogenous RNA network in periodontitis

“…Salivary HSPAs may contribute to protection against oral microorganisms and maintain gingival health; extracellular HSPAs may nevertheless induce gingivitis under certain conditions, turn gingivitis into periodontitis and accelerate the loss of periodontal bone . CTNNBIP1 (catenin, beta interacting protein 1, also known as ICAT; gene ID: 56998), shown to be downregulated expressed in periodontitis, is a candidate gene that inhibits the transcriptional activity of nuclear β‐catenin . The activation of nuclear β‐catenin can inhibit the noncanonical Wnt pathway, leading to increased proliferation but reduced osteogenic differentiation of periodontal ligament stem cells .…”