title: Sox2 promotes tamoxifen resistance in breast cancer cells.
abstract: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Piva
authors.forename: Giacomo
authors.initials: G
authors.lastname: Domenici
authors.forename: Oihana
authors.initials: O
authors.lastname: Iriondo
authors.forename: Miriam
authors.initials: M
authors.lastname: Rábano
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Simões
authors.forename: Valentine
authors.initials: V
authors.lastname: Comaills
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Barredo
authors.forename: Jose A
authors.initials: JA
authors.lastname: López-Ruiz
authors.forename: Ignacio
authors.initials: I
authors.lastname: Zabalza
authors.forename: Robert
authors.initials: R
authors.lastname: Kypta
authors.forename: Maria d M
authors.initials: Md
authors.lastname: Vivanco
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D012008:Recurrence; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D055748:SOXB1 Transcription Factors; D051153:Wnt Proteins; D013629:Tamoxifen