Open AccessSox2 promotes tamoxifen resistance in breast cancer cells
Author(s) -
Piva Marco,
Domenici Giacomo,
Iriondo Oihana,
Rábano Miriam,
Simões Bruno M,
Comaills Valentine,
Barredo Inmaculada,
LópezRuiz Jose A,
Zabalza Ignacio,
Kypta Robert,
Vivanco Maria d M
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201303411
Subject(s) - sox2 , tamoxifen , cancer research , progenitor cell , wnt signaling pathway , cancer stem cell , biology , breast cancer , stem cell , medicine , cancer , microbiology and biotechnology , signal transduction , genetics , gene , transcription factor
Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo‐ and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen‐resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo . Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2‐expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2‐dependent activation of Wnt signalling in cancer stem/progenitor cells.