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Cited by 34Cancer Cells and MetastasisMechanisms of cancer metastasisBreast Cancer Treatment Studies

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

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Krstic, Milica, Kolendowski, Bart, Cecchini, Matthew J, Postenka, Carl O, Hassan, Haider M, Andrews, Joseph, MacMillan, Connor D, Williams, Karla C +5 more·2019·The Journal of Pathology
DOI 10.1002/path.5245PMC PMC6593675
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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.

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  • TBX3 can either promote tumor development or suppress tumor progression, depending on the tumor type.

    “It has been reported TBX3 can either promote tumor development or suppress tumor progression, depending on the tumor type.[12, 21-24]”

    From TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis (2021) · cites this paper as [24]

    The Discussion (page unavailable) proposes that TBX3 promotes progression from low-grade DCIS to invasive breast cancer, supporting the tumor-promoting part of the claim. The paper does not report TBX3 suppressing tumor progression in another tumor type, so it does not establish the claimed tumor-type-dependent reversal. (LLM, conf=0.88)

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Authors
Krstic, M., Kolendowski, B., Cecchini, M. J., Postenka, C. O., Hassan, H. M., Andrews, J., MacMillan, C. D., Williams, K. C., Leong, H. S., Brackstone, M., Torchia, J., Chambers, A. F., & Tuck, A. B.
Affiliations
  • Western University (CA)
  • University of British Columbia (CA)
  • Mayo Clinic (US)
Corresponding author
Tuck, Alan B
ORCID
Venue
The Journal of Pathology
Publisher
Wiley
Published
2019-04-08
Volume
248
Issue
2
Pages
191-203
ISSN
  • 0022-3417 (ISSN-L)
  • 1096-9896
DOI
10.1002/path.5245
PMC
PMC6593675
OpenAlex
W2913719755
Cited by
34
References
2
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 9 · 2021: 9 · 2020: 3 · 2019: 4
FWCI
2.61
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Pathology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Scholarship@Western (Western University) (submittedVersion)
Funders
  • Canadian Institutes of Health Research (PJT‐155982)
  • Ontario Institute for Cancer Research
  • Breast Cancer Society of Canada
  • Government of Ontario
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
TBX3, Slug, TWIST1, epithelial-mesenchymal transition, ductal carcinoma in situ, breast cancer progression, breast cancer invasion, cell migration, transcriptional regulation, basement membrane degradation, early breast cancer
MeSH terms
Snail Family Transcription Factors, Breast Neoplasms, Carcinoma, Intraductal, Noninfiltrating, Cell Movement, Female, Humans, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Signal Transduction, Up-Regulation, Gene Expression Regulation, Neoplastic, Disease Progression, T-Box Domain Proteins, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Neoplasm Grading

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