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Cited by 46Wnt/β-catenin signaling in development and cancerBone and Dental Protein StudiesCancer Cells and Metastasis

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Wnt–β-catenin–Tcf-4 signalling-modulated invasiveness is dependent on osteopontin expression in breast cancer

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Ravindranath, A, Yuen, H-F, Chan, K-K, Grills, C, Fennell, D A, Lappin, T R, El-Tanani, M·2011·British Journal of Cancer
DOI 10.1038/bjc.2011.269PMC PMC3170969
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Abstract

BACKGROUND: We have previously demonstrated that Tcf-4 regulates osteopontin (OPN) in rat breast epithelial cells, Rama37. In this report, we have examined the importance of this regulation in human breast cancer. METHODS: The regulatory roles of Tcf-4 on cell invasion and OPN expression were investigated. The mRNA expression of Tcf-4 and OPN, and survival of breast cancer patients were correlated. RESULTS: Tcf-4 enhanced cell invasion in both MCF10AT and MDA MB 231 breast cancer cells by transcriptionally activating OPN expression. Osteopontin was activated by Wnt signalling in MDA MB 231 cells. Paradoxical results on Tcf-4-regulated OPN expression in MCF10AT (activation) and Rama37 (repression) cells were shown to be a result of differential Wnt signalling competency in MCF10AT and Rama37 cells. High levels of OPN and Tcf-4 mRNA expression were significantly associated with survival in breast cancer patients. Most importantly, Tcf-4-positive patients had a poorer prognosis when OPN was overexpressed, while OPN-negative patients had a better prognosis when Tcf-4 was overexpressed. CONCLUSION: Our results suggest that Tcf-4 can act as a repressor or activator of breast cancer progression by regulating OPN expression in a Wnt-dependent manner and that Tcf-4 and OPN together may be a novel prognostic indicator for breast cancer progression.

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  • Five activating alterations in Wnt-TGFβ-class (FZD7, FZD6, TCF4, FRAT2 and ARBB2) have been related to Wnt activation in cancer.

    “among which five of them (FZD7, FZD6, TCF4, FRAT2 and ARBB2) have been related to Wnt activation in cancer (20-25)”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [22]

    The Conclusion section links Tcf-4 to Wnt signalling in breast cancer, supporting the TCF4 portion of the claim. It does not identify five activating alterations or link FZD7, FZD6, FRAT2, or ARBB2 to Wnt activation; it says there is no evidence for specific mutations in this context. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Several genes dysregulated in Wnt-TGFβ-class characterize Wnt-signaling activation in cancer.

    “In contrast, several genes dysregulated in Wnt-TGFβ-class characterize Wnt-signaling activation in cancer (20-25) (Fig. 6).”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [22]

    The Conclusion (page not provided) reports aberrant downregulation of the Wnt inhibitor WIF-1 and evidence of Wnt-pathway activation in breast cancer. It does not identify a Wnt–TGFβ gene class or show that several genes dysregulated in that class characterize Wnt activation. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • FZD7 and TCF4 upregulation has been previously described to activate Wnt signaling in the absence of β-catenin mutations.

    “This is the case of both FZD7(21) and TCF4(22) which upregulation has been previously described to activate Wnt signaling in the absence of β-catenin mutations.”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [22]

    The Results section (‘Tcf-4-induced OPN may be dependent on the competency of Wnt signalling’; page unavailable) reports that Tcf-4 overexpression activated a Wnt-signalling reporter in MCF10AT cells, supporting the TCF4 portion attributed to this paper. The paper says there is no evidence for specific mutations in the breast-cancer context, but it does not establish that the tested cells lacked β-catenin mutations. FZD7 is attached to a different citation in the citing sentence and is not assessed here. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Metadata

Authors
Ravindranath, A., Yuen, H.-F., Chan, K.-K., Grills, C., Fennell, D. A., Lappin, T. R., & El-Tanani, M.
Affiliations
Queen's University Belfast (GB)
ORCID
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2011-07-19
Volume
105
Issue
4
Pages
542-551
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
DOI
10.1038/bjc.2011.269
PMC
PMC3170969
OpenAlex
W2018703433
Cited by
46
References
0
Citations by year
2026: 4 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 6 · 2015: 4 · 2014: 3 · 2013: 7 · 2012: 3
FWCI
1.69
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Cancer (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Leicester Research Archive (University of Leicester) (submittedVersion)
  • Research Portal (Queen's University Belfast) (submittedVersion)
Funders
Cancer Research UK
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Bone and Dental Protein Studies
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
Wnt signaling, β-catenin, TCF4, osteopontin, breast cancer, cell invasion, transcriptional regulation, prognostic factors, patient survival, MDA-MB-231 cells
MeSH terms
Transcription Factor 4, Breast Neoplasms, Female, Humans, Neoplasm Invasiveness, Prognosis, Transcription Factors, Blotting, Western, Signal Transduction, Up-Regulation, Gene Expression Regulation, Neoplastic, Polymerase Chain Reaction, Protein Array Analysis, Chromatin Immunoprecipitation, Wnt Proteins, beta Catenin, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Osteopontin

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