β-catenin haploinsufficiency promotes mammary tumorigenesis in an ErbB2-positive basal breast cancer model

Bui Tung, Babette Schade, Robert Cardiff, Olulanu H. Aina, Virginie Sanguin-Gendreau, William J. Muller

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Aberrant activation of β-catenin through its activity as a transcription factor has been observed in a large proportion of human malignancies. Despite the improved understanding of the β-catenin signaling pathway over the past three decades, attempts to develop therapies targeting β-catenin remain challenging, and none of these targeted therapies have advanced to the clinic. In this study, we show that part of the challenge in antagonizing β-catenin is caused by its dual functionality as a cell adhesion molecule and a signaling molecule. In a mouse model of basal ErbB2 receptor tyrosine kinase 2 (ErbB2)-positive breast cancer (ErbB2KI), which exhibits aberrant β-catenin nuclear signaling, β-catenin haploinsufficiency induced aggressive tumor formation and metastasis by promoting the disruption of adherens junctions, dedifferentiation, and an epithelial to mesenchymal transition (EMT) transcriptional program. In contrast to the accelerated tumor onset observed in the haploid-insufficient ErbB2 tumors, deletion of both β-catenin alleles in the ErbB2KI model had only a minor impact on tumor onset that further correlated with the retention of normal adherens junctions. We further showed that retention of adherens junctional integrity was caused by the up-regulation of the closely related family member plakoglobin (γ-catenin) that maintained both adherens junctions and the activation of Wnt target genes. In contrast to the ErbB2KI basal tumor model, modulation of β-catenin levels had no appreciable impact on tumor onset in an ErbB2-driven model of luminal breast cancer [murine mammary tumor virus promoter (MMTV-NIC)]. These observations argue that the balance of junctional and nuclear β-catenin activity has a profound impact on tumor progression in this basal model of ErbB2-positive breast cancer.

Original languageEnglish (US)
Pages (from-to)E707-E716
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number5
DOIs
StatePublished - Jan 31 2017

Fingerprint

Haploinsufficiency
Catenins
Carcinogenesis
Breast
Breast Neoplasms
Adherens Junctions
Neoplasms
Gammaretrovirus
TYK2 Kinase
gamma Catenin
Mouse mammary tumor virus
Epithelial-Mesenchymal Transition
Haploidy
Cell Adhesion Molecules
Carcinogens
Transcription Factors
Up-Regulation
Alleles
Neoplasm Metastasis

Keywords

  • Beta-catenin
  • Breast cancer
  • Cell junction
  • ErbB2
  • Transgenic model

ASJC Scopus subject areas

  • General

Cite this

β-catenin haploinsufficiency promotes mammary tumorigenesis in an ErbB2-positive basal breast cancer model. / Tung, Bui; Schade, Babette; Cardiff, Robert; Aina, Olulanu H.; Sanguin-Gendreau, Virginie; Muller, William J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 5, 31.01.2017, p. E707-E716.

Research output: Contribution to journalArticle

Tung, Bui ; Schade, Babette ; Cardiff, Robert ; Aina, Olulanu H. ; Sanguin-Gendreau, Virginie ; Muller, William J. / β-catenin haploinsufficiency promotes mammary tumorigenesis in an ErbB2-positive basal breast cancer model. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 5. pp. E707-E716.
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