Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

F. Takahashi, N. Chiba, K. Tajima, Tetsu Hayashida, T. Shimada, M. Takahashi, H. Moriyama, E. Brachtel, E. J. Edelman, S. Ramaswamy, S. Maheswaran

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The B-cell translocation gene-2 (BTG2), a p53-inducible gene, is suppressed in mammary epithelial cells during gestation and lactation. In human breast cancer, decreased BTG2 expression correlates with high tumor grade and size, p53 status, blood and lymph vessel invasion, local and metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 has a critical role in disease progression. To analyze the role of BTG2 in breast cancer progression, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhances the motility of cells in vitro and tumor growth and metastasis in vivo. The effects of BTG2 knockdown are mediated through stabilization of the human epidermal growth factor receptor (HER) ligands neuregulin and epiregulin and activation of the HER2 and HER3 receptors, leading to elevated AKT phosphorylation. Suppression of HER activation using the tyrosine kinase inhibitor lapatinib abrogates the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.

Original languageEnglish
Pages (from-to)3084-3095
Number of pages12
JournalOncogene
Volume30
Issue number27
DOIs
Publication statusPublished - 2011 Jul 7
Externally publishedYes

Fingerprint

B-Lymphocytes
Breast Neoplasms
Gene Expression
Gene Knockdown Techniques
Therapeutics
Genes
Cell Movement
Breast
Epithelial Cells
Neuregulins
lapatinib
Neoplasm Metastasis
Neoplasms
p53 Genes
Lymph
Lactation
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Blood Vessels
Disease Progression

Keywords

  • breast cancer
  • BTG2
  • ErbB/HER pathway
  • invasion
  • metastasis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib. / Takahashi, F.; Chiba, N.; Tajima, K.; Hayashida, Tetsu; Shimada, T.; Takahashi, M.; Moriyama, H.; Brachtel, E.; Edelman, E. J.; Ramaswamy, S.; Maheswaran, S.

In: Oncogene, Vol. 30, No. 27, 07.07.2011, p. 3084-3095.

Research output: Contribution to journalArticle

Takahashi, F, Chiba, N, Tajima, K, Hayashida, T, Shimada, T, Takahashi, M, Moriyama, H, Brachtel, E, Edelman, EJ, Ramaswamy, S & Maheswaran, S 2011, 'Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib', Oncogene, vol. 30, no. 27, pp. 3084-3095. https://doi.org/10.1038/onc.2011.24
Takahashi, F. ; Chiba, N. ; Tajima, K. ; Hayashida, Tetsu ; Shimada, T. ; Takahashi, M. ; Moriyama, H. ; Brachtel, E. ; Edelman, E. J. ; Ramaswamy, S. ; Maheswaran, S. / Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib. In: Oncogene. 2011 ; Vol. 30, No. 27. pp. 3084-3095.
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