Abstract 4372: Radiation induces Notch-dependent de novo generation of breast cancer stem cells via expression of OCT-4/SOX2/NANOG

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-04, Vol.71 (8_Supplement), p.4372-4372
• Main Authors: Lagadec, Chann H., Della Donna, Lorenza, Vlashi, Erina, Dekmezian, Carmen, Brocks, Tania, Pajonk, Frank
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-4372

Like in normal tissues, the self-renewal of cancer stem cells (CSCs) might be also under tight control of developmental pathway like the Notch, Wnt, Sonic Hedgehog or TGFβ pathways. The Notch pathway plays an important role in normal breast development, cell fate, and normal stem cell self-renewal, and its deregulation has been shown to play a role in cancer. Aberrant Notch signaling has been implicated in the development and progression of both preinvasive ductal carcinomas in situ and invasive breast cancers. Interestingly, in breast cancer, the Notch pathway plays major role for CSCs maintenance. We previously published that BCSCs (Breast Cancer Stem Cells) are relatively resistant to radiation and we demonstrated a link between BCSCs radio-resistance and the Notch pathway. Irradiation of MCF-7 and T47D cells increased the number of CSCs and this correlated with the induction of Notch signaling protein expression in a dose- and time-dependent manner. Jagged 1 expression was quickly (1h) increased 28-fold after 2Gy, DLL1 expression was increased 15-fold, 3 to 6h after irradiation with 2 or 4 Gy, Notch 2 expression was increased 16-fold 6h after 2, 4, 6 or 8 Gy, while DLL3 was increased 10-fold after the highest doses (6 to 12 Gy). Inhibition of Notch signaling pathway by a γ-secreatase inhibitor prevented enrichment for CSCs and reduced radiation-induced Notch protein expression. Most importantly, we demonstrated that radiation-induced Notch signaling contributes to the phenotype plasticity of BCSCs and their progeny. Using 2 different cancer stem cell markers (low proteasome activity and ALDH1) to found that radiation causes de novo generation of induced BCSCs (iBCSCs) from non-tumorigenic cells and this correlated with radiation-induced the expression of OCT-4, SOX2, and NANOG, key transcription factors of used to generate induced pluripotent stem cells (iPS cells). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4372. doi:10.1158/1538-7445.AM2011-4372