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Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells

Abstract

Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-α (ER-α)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-α status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-α-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-α status.

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Acknowledgements

The study is supported by grants from INSERM, la Ligue Nationale Contre le Cancer (Equipe labellisée 2006), le Ministère de l'Education Nationale and the Région Nord/Pas-de-Calais. Chann Lagadec was the recipient of a fellowship from the Association pour la Recherche sur le Cancer (ARC).

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Correspondence to X Le Bourhis.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Lagadec, C., Adriaenssens, E., Toillon, R. et al. Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells. Oncogene 27, 1472–1477 (2008). https://doi.org/10.1038/sj.onc.1210749

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