title: 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.
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India. Electronic address: nupurmukherjee10@gmail.com.
authors.forename: Nupur
authors.initials: N
authors.lastname: Mukherjee
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India. Electronic address: hemantika2007@gmail.com.
authors.forename: Hemantika
authors.initials: H
authors.lastname: Dasgupta
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India. Electronic address: rittwikab@gmail.com.
authors.forename: Rittwika
authors.initials: R
authors.lastname: Bhattacharya
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India. Electronic address: dbln.pl@gmail.com.
authors.forename: Debolina
authors.initials: D
authors.lastname: Pal
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India. Electronic address: ritu.dona@gmail.com.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Roy
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India. Electronic address: saimulislam80@gmail.com.
authors.forename: Saimul
authors.initials: S
authors.lastname: Islam
authors.affiliation: Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India. Electronic address: nalam@cnci.org.in.
authors.forename: Neyaz
authors.initials: N
authors.lastname: Alam
authors.affiliation: Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India. Electronic address: jbiswas@cnci.org.in.
authors.forename: Jaydip
authors.initials: J
authors.lastname: Biswas
authors.affiliation: Department of Pathology, Sushruta Nagar, Darjeeling, West Bengal, India. Electronic address: anuproy99@yahoo.com.
authors.forename: Anup
authors.initials: A
authors.lastname: Roy
authors.affiliation: Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata, 700 063 Kolkata, West Bengal, India. Electronic address: susantarc@gmail.com.
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India. Electronic address: ckpanda.cnci@gmail.com.
authors.forename: Chinmay Kumar
authors.initials: CK
authors.lastname: Panda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D009154:Mutation; D010766:Phosphorylation; D011379:Prognosis; D015533:Transcriptional Activation; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; C411982:CTNNBIP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C067857:MCC protein, human
keywords: Breast cancer; Breast cancer subtypes; EGFR/MYC/CCND1; MCC/CTNNBIP1; Nuclear β-catenin; p-β-catenin(Y654)