TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β-Catenin Pathway upon LPS Stimulation

Anat Rec (Hoboken). 2017 Jul;300(7):1219-1229. doi: 10.1002/ar.23590. Epub 2017 Mar 30.


Bacteria/virus-induced chronic inflammation is involved in both tumor initiation and tumor progression. Toll-like receptor 4 (TLR4) has been implicated in the development of several types of cancer. In this study, we explored the impact of TLR4 activation by lipopolysaccharide (LPS) on breast cancer metastasis and associated signaling molecules. We first examined TLR4 expression levels in breast tissue using a human breast tissue microarray and breast cell lines. We then studied the role of TLR4 activation by LPS stimulation in breast cancer metastasis using both in vitro and in vivo models. Finally, we investigated signaling molecules involved in the process using Western blotting and fluorescent immunohistochemistry staining. The results showed that TLR4 expression levels increased in breast cancer tissue compared to normal breast tissue. In addition, our results also showed that TLR4 pathway activation by LPS stimulation in MCF7 and MDA-MB-231 breast cancer cells caused the following actions: (1) promotes migration of breast cancer cells, (2) triggers the β-catenin signaling pathway via PI3K/Akt/GSK3β, and (3) promotes transcription of downstream β-catenin target genes leading to breast cancer metastasis. This study substantiates and further extends the relationship between TLR4 activation by LPS and breast cancer using both in vitro and in vivo models. The results suggest that the Akt/GSK3β/β-catenin signal transduction pathway may serve as a viable clinical treatment target in breast cancer. Anat Rec, 300:1219-1229, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: Akt/GSK3β/β-catenin pathway; LPS; TLR4; breast cancer.

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Humans
  • Lipopolysaccharides / pharmacology*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism*


  • CTNNB1 protein, human
  • Lipopolysaccharides
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • beta Catenin
  • Phosphatidylinositol 3-Kinases
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt