Sox2 promotes tamoxifen resistance in breast cancer cells

• Published in: EMBO molecular medicine 2014-01, Vol.6 (1), p.66-79
• Main Authors: Piva, Marco, Domenici, Giacomo, Iriondo, Oihana, Rábano, Miriam, Simões, Bruno M, Comaills, Valentine, Barredo, Inmaculada, López‐Ruiz, Jose A, Zabalza, Ignacio, Kypta, Robert, Vivanco, Maria d M
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Hormonal - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Cancer therapies; Cell growth; Chemotherapy; Dehydrogenases; Drug Resistance, Neoplasm - genetics; Ectopic expression; EMBO03; EMBO39; Endocrine therapy; Endoplasmic Reticulum - metabolism; Ethanol; Female; Gene expression; Humans; Hypotheses; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - metabolism; Progenitor cells; Radiation therapy; Recurrence; Research Article; RNA Interference; Signal transduction; Sox2; Sox2 protein; SOXB1 Transcription Factors - antagonists & inhibitors; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Stem cells; Survival Analysis; Tamoxifen; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; tamoxifen resistance; Transplantation, Heterologous; Transplants & implants; Tumors; Wnt protein; Wnt Proteins - metabolism; Wnt Signaling Pathway - drug effects; wnt signalling
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201303411

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. Synopsis The development of Tam‐resistance in breast cancer is shown to be driven by Sox2‐dependent activation of Wnt signalling in cancer stem cells. Combining hormone therapy and Wnt secretion inhibitors might thus provide a novel strategy to treat breast cancer. Cancer stem cells play a role in the development of tamoxifen resistance. Sox2 expression is increased in tamoxifen‐resistant breast cancer cells. Sox2 inhibition restores cell sensitivity to tamoxifen. Sox2 is a biomarker for tamoxifen resistance. Combining hormone therapy with Wnt or Sox2 inhibitors may help prevent breast cancer recurrence. Graphical Abstract The development of Tam‐resistance in breast cancer is shown to be driven by Sox2‐dependent activation of Wnt signalling in cancer stem cells. Combining hormone therapy and Wnt secretion inhibitors might thus provide a novel strategy to treat breast cancer.