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

Authors
Yoo, Young A.Kim, Yeul HongKim, Jun SukSeo, Jae Hong
Issue Date
3월-2008
Publisher
ELSEVIER SCIENCE BV
Keywords
tamoxifen; Akt; transforming growth factor-beta; breast cancer
Citation
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v.1783, no.3, pp.438 - 447
Indexed
SCIE
SCOPUS
Journal Title
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume
1783
Number
3
Start Page
438
End Page
447
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/124032
DOI
10.1016/j.bbamcr.2007.12.001
ISSN
0167-4889
Abstract
Development of acquired resistance to tamoxifen is a major clinical problem during endocrine treatment in estrogen receptor positive breast cancer. Transforming growth factor-beta 1 (TGF-beta) 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-beta 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-beta 1 secretion, TGF-beta-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-Akt(Myr)) rendered MCF-7 cells resistant to activation by TGF-beta and the growth inhibitory effects of 4-OHT, while over-expression of kinase-dead Akt (Myc-Akt(K179M)) or LY294002 treatment of Tam-R cells enhanced TGF-beta activation and blocked cell growth. These results suggest that suppression of TGF+ signaling by activated Akt is correlated with the development of tamoxifen resistance in breast cancer. (c) 2007 Elsevier B.V. All rights reserved.
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