Regulation of breast cancer-induced bone lesions by β-catenin protein signaling

Yan Chen, Heidi Y. Shi, Stuart R. Stock, Paula H. Stern, Ming Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Breast cancer patients have an extremely high rate of bone metastases. Morphological analyses of the bones in most of the patients have revealed the mixed bone lesions, comprising both osteolytic and osteoblastic elements. β-Catenin plays a key role in both embryonic skeletogenesis and postnatal bone regeneration. Although this pathway is also involved in many bone malignancy, such as osteosarcoma and prostate cancer-induced bone metastases, its regulation of breast cancer bone metastases remains unknown. Here, we provide evidence that the β-catenin signaling pathway has a significant impact on the bone lesion phenotype. In this study, we established a novel mouse model of mixed bone lesions using intratibial injection of TM40D-MB cells, a breast cancer cell line that is highly metastatic to bone. Wefound that both upstream and downstream molecules of the β-catenin pathway are up-regulated in TM40D-MB cells compared with non-bone metastaticTM40Dcells.TM40D-MBcells also have a higher T cell factor (TCF) reporter activity than TM40D cells. Inactivation of β-catenin in TM40D-MB cells through expression of a dominant negative TCF4 not only increasesosteoclastdifferentiationinatumor- boneco-culturesystem and enhances osteolytic bone destruction in mice, but also inhibits osteoblast differentiation. Surprisingly, although tumor cellsoverexpressing β-catenindidinduceaslightincreaseofosteoblast differentiation in vitro, these cells display a minimal effect on osteoblastic bone formation in mice. These data collectively demonstrate that β-catenin acts as an important determinant in mixed bone lesions, especially in controlling osteoblastic effect within tumor-harboring bone environment.

Original languageEnglish (US)
Pages (from-to)42575-42584
Number of pages10
JournalJournal of Biological Chemistry
Issue number49
StatePublished - Dec 9 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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