α-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-κB signalling

Hai-Long Piao; Yuan Yuan; Min Wang; Yutong Sun; Han Liang; Li Ma

doi:10.1038/ncb2909

α-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-κB signalling

Nat Cell Biol. 2014 Mar;16(3):245-54. doi: 10.1038/ncb2909. Epub 2014 Feb 9.

Authors

Hai-Long Piao¹, Yuan Yuan², Min Wang¹, Yutong Sun³, Han Liang⁴, Li Ma⁵

Affiliations

¹ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center Houston Texas 77030 USA.
² 1] Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center Houston Texas 77030 USA [2] Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine Houston Texas 77030 USA.
³ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston Texas 77030 USA.
⁴ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center Houston Texas 77030 USA.
⁵ 1] Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center Houston Texas 77030 USA [2] Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston Houston Texas 77030 USA.

PMID: 24509793
PMCID: PMC3943677
DOI: 10.1038/ncb2909

Abstract

Basal-like breast cancer is a highly aggressive tumour subtype associated with poor prognosis. Aberrant activation of NF-κB signalling is frequently found in triple-negative basal-like breast cancer cells, but the cause of this activation has remained elusive.Here we report that α-catenin functions as a tumour suppressor in E-cadherin-negative basal-like breast cancer cells by inhibiting NF-κB signalling. Mechanistically, α-catenin interacts with the IκBα protein, and stabilizes IκBα by inhibiting its ubiquitylation and its association with the proteasome. This stabilization in turn prevents nuclear localization of RelA and p50, leading to decreased expression of TNF-α, IL-8 and RelB. In human breast cancer, CTNNA1 expression is specifically downregulated in the basal-like subtype, correlates with clinical outcome and inversely correlates with TNF and RELB expression. Taken together, these results uncover a previously undescribed mechanism by which the NF-κB pathway is activated in E-cadherin-negative basal-like breast cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus
Animals
Antigens, CD
Base Sequence
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cadherins / metabolism*
Cell Line, Tumor
Cell Nucleus / metabolism
Cell Proliferation
Down-Regulation
Female
Humans
I-kappa B Proteins / metabolism
Mice
Mice, Nude
Molecular Sequence Data
NF-KappaB Inhibitor alpha
NF-kappa B p50 Subunit / metabolism
Neoplasm Transplantation
Neoplasms, Basal Cell / metabolism*
Neoplasms, Basal Cell / pathology
Promoter Regions, Genetic
Proteasome Endopeptidase Complex / metabolism
Protein Stability
Signal Transduction
Transcription Factor RelA / metabolism
Transcription Factor RelB / genetics*
Transcription Factor RelB / metabolism
Tumor Burden
Tumor Suppressor Proteins / physiology
Ubiquitination
alpha Catenin / physiology*

Substances

Antigens, CD
CDH1 protein, human
Cadherins
I-kappa B Proteins
NF-kappa B p50 Subunit
NFKBIA protein, human
Nfkbia protein, mouse
RELA protein, human
RELB protein, human
Transcription Factor RelA
Tumor Suppressor Proteins
alpha Catenin
NF-KappaB Inhibitor alpha
Transcription Factor RelB
Proteasome Endopeptidase Complex

Abstract

Publication types

MeSH terms

Substances

Grants and funding