TBX3 promotes progression of pre-invasive breast cancer cells by inducing EMT and directly up-regulating SLUG

Authors

Milica Krstic, Schulich School of Medicine & Dentistry
Bart Kolendowski, Schulich School of Medicine & Dentistry
Matthew J. Cecchini, Schulich School of Medicine & Dentistry
Carl O. Postenka, Schulich School of Medicine & Dentistry
Haider M. Hassan, Schulich School of Medicine & Dentistry
Joseph Andrews, Schulich School of Medicine & DentistryFollow
Connor D. MacMillan, The University of British Columbia
Karla C. Williams, The University of British Columbia
Hon S. Leong, Mayo Clinic
Muriel Brackstone, Schulich School of Medicine & Dentistry
Joseph Torchia, Schulich School of Medicine & Dentistry
Ann F. Chambers, Schulich School of Medicine & Dentistry
Alan B. Tuck, Schulich School of Medicine & Dentistry

Document Type

Article

Publication Date

6-1-2019

Journal

Journal of Pathology

Volume

248

Issue

2

First Page

191

Last Page

203

URL with Digital Object Identifier

10.1002/path.5245

Abstract

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.