TBX3 promotes progression of pre-invasive breast cancer cells by inducing EMT and directly up-regulating SLUG.
Breast Neoplasms
/ genetics
Carcinoma, Intraductal, Noninfiltrating
/ genetics
Cell Line, Tumor
Cell Movement
Disease Progression
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
Humans
Middle Aged
Neoplasm Grading
Neoplasm Invasiveness
Neoplasm Staging
Signal Transduction
Snail Family Transcription Factors
/ genetics
T-Box Domain Proteins
/ genetics
Up-Regulation
SLUG
TBX3
breast cancer
ductal carcinoma in situ (DCIS)
epithelial-to-mesenchymal transition (EMT)
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
20
09
2018
revised:
22
01
2019
accepted:
25
01
2019
pubmed:
31
1
2019
medline:
14
4
2020
entrez:
31
1
2019
Statut:
ppublish
Résumé
The acquisition of cellular invasiveness by breast epithelial cells and subsequent transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step in breast cancer progression. Little is known about the molecular dynamics governing this transition. We have previously shown that overexpression of the transcriptional regulator TBX3 in DCIS-like cells increases survival, growth, and invasiveness. To explore this mechanism further and assess direct transcriptional targets of TBX3 in a high-resolution, isoform-specific context, we conducted genome-wide chromatin-immunoprecipitation (ChIP) arrays coupled with transcriptomic analysis. We show that TBX3 regulates several epithelial-mesenchymal transition (EMT)-related genes, including SLUG and TWIST1. Importantly, we demonstrate that TBX3 is a direct regulator of SLUG expression, and SLUG expression is required for TBX3-induced migration and invasion. Assessing TBX3 by immunohistochemistry in early-stage (stage 0 and stage I) breast cancers revealed high expression in low-grade lesions. Within a second independent early-stage non-high-grade cohort, we observed an association between TBX3 level in the DCIS and size of the invasive focus. Additionally, there was a positive correlation between TBX3 and SLUG, and TBX3 and TWIST1 in the invasive carcinoma. Pathway analysis revealed altered expression of several proteases and their inhibitors, consistent with the ability to degrade basement membrane in vivo. These findings strongly suggest the involvement of TBX3 in the promotion of invasiveness and progression of early-stage pre-invasive breast cancer to invasive carcinoma through the low-grade molecular pathway. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Identifiants
pubmed: 30697731
doi: 10.1002/path.5245
pmc: PMC6593675
doi:
Substances chimiques
SNAI1 protein, human
0
Snail Family Transcription Factors
0
T-Box Domain Proteins
0
TBX3 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
191-203Subventions
Organisme : Canadian Institutes of Cancer Research (CIHR)
ID : PJT-155982
Pays : International
Informations de copyright
© 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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