The functional implications of Akt activity and TGF-β signaling in tamoxifen-resistant breast cancer

Young A. Yoo, Yeul Hong Kim, Jun Suk Kim, Jae Hong Seo

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Development of acquired resistance to tamoxifen is a major clinical problem during endocrine treatment in estrogen receptor positive breast cancer. Transforming growth factor-β1 (TGF-β) has been implicated in tamoxifen-induced cellular signaling in breast cancer, and increased Akt activation is associated with tamoxifen-resistant cell types. We hypothesized that the relationship between TGF-β and Akt signaling may be involved in the development and progression of tamoxifen resistance. Tamoxifen-resistant (Tam-R) cells were established from parental MCF-7 cells by continuously exposing them to 4-hydroxytamoxifen (4-OHT). Tam-R cells were associated with a decrease in TGF-β1 secretion, TGF-β-mediated transcriptional response, and growth inhibitory effects of 4-OHT. Tam-R cells expressed significantly higher levels of phosphorylated Akt and lower levels of phosphorylated Smad 3 in both the absence and presence of 4-OHT when compared to MCF-7 cells treated with 4-OHT. Ectopic expression of constitutively active Akt (Myc-AktMyr) rendered MCF-7 cells resistant to activation by TGF-β and the growth inhibitory effects of 4-OHT, while over-expression of kinase-dead Akt (Myc-AktK179M) or LY294002 treatment of Tam-R cells enhanced TGF-β activation and blocked cell growth. These results suggest that suppression of TGF-β signaling by activated Akt is correlated with the development of tamoxifen resistance in breast cancer.

Original languageEnglish
Pages (from-to)438-447
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1783
Issue number3
DOIs
Publication statusPublished - 2008 Mar 1
Externally publishedYes

Keywords

  • Akt
  • Breast cancer
  • Tamoxifen
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Biophysics

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