Repression of E-cadherin by SNAIL, ZEB1, and TWIST in invasive ductal carcinomas of the breast: a cooperative effort?
It has been suggested that down-regulation of E-cadherin in invasive breast ductal carcinomas is mediated by the aberrant expression of several of its transcriptional repressors, but their inhibitory role and clinical importance are not yet well established. We investigated gene and protein expression patterns of the E-cadherin repressors SNAIL, ZEB1, and TWIST in relation to clinicopathologic parameters, in a series of 88 patients with invasive breast ductal carcinomas. Up-regulation of SNAIL messenger RNA (P = .008) and down-regulation of TWIST (P = .022) were associated with triple-negative tumors, whereas ZEB1 gene expression was more frequent in hormone-positive tumors (P = .004). Loss of E-cadherin was found in 19% of the tumors, but it did not correlate with aberrant expression of any of the repressors investigated herein. Nonetheless, we found that ZEB-1 protein overexpression inversely correlated with high tumor grade (P = .018), nuclear grade (P = .002), and presence of lymph nodes (P = .001), and these data were consistent with the gene expression data for ZEB1. Clinically, down-regulation of ZEB1 messenger RNA was associated with poor overall survival (P = .011) and disease-free survival (P = .053), whereas patients with TWIST negative tumors had a worse overall survival (P = .008) and disease-free survival (P = .006). Our data indicate that deregulation of TWIST is somehow important in the aggressiveness of triple-negative carcinomas and poor patient outcome, whereas down-regulation of ZEB1 seems to play a role in tumor spread, metastases, and poor survival.
Montserrat
Núria
N
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, 08025 Barcelona, Spain.
Gallardo
Alberto
A
Escuin
Daniel
D
Catasus
Lluís
L
Prat
Jaime
J
Gutiérrez-Avignó
Francisco José
FJ
Peiró
Gloria
G
Barnadas
Agustí
A
Lerma
Enrique
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000502:physiology*; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1