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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Broaddus VC, Dansen TB, Abayasiriwardana KS, Wilson SM, Finch AJ, Swigart LB et al. (2005). Bid mediates apoptotic synergy between tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and DNA damage. J Biol Chem 280: 12486–12493.
Chopin V, Slomianny C, Hondermarck H, Le Bourhis X . (2004). Synergistic induction of apoptosis in breast cancer cells by cotreatment with butyrate and TNF-alpha, TRAIL, or anti-Fas agonist antibody involves enhancement of death receptors' signaling and requires P21(waf1). Exp Cell Res 298: 560–573.
Duiker EW, Mom CH, de Jong S, Willemse PH, Gietema JA, van der Zee AG et al. (2006). The clinical trail of TRAIL. Eur J Cancer 42: 2233–2240.
Gelman EP . (1997). Tamoxifen for the treatment of malignancies other than breast and endometrial carcinoma. Semin Oncol 24 (Suppl): S65–S70.
Grambihler A, Higuchi H, Bronk SF, Gores GJ . (2003). cFLIP-L inhibits p38 MAPK activation: an additional anti-apoptotic mechanism in bile acid-mediated apoptosis. J Biol Chem 278: 26831–26837.
Hawkins RA, Arends MJ, Ritchie AA, Langdon S, Miller WR . (2000). Tamoxifen increases apoptosis but does not influence markers of proliferation in an MCF-7 xenograft model of breast cancer. Breast J 9: 96–106.
Jordan VC . (1992). The strategic use of antiestrogens to control the development and growth of breast cancer. Cancer 70 (Suppl): S977–S982.
Kallio A, Zheng A, Dahllund J, Heiskanen KM, Härkönen P . (2005). Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells. Apoptosis 10: 1395–1410.
LeBlanc HN, Ashkenazi A . (2003). Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 10: 66–75.
Lover RR . (1989). Tamoxifen therapy in primary breast cancer: biology, efficacy, and side effects. J Clin Oncol 7: 803–815.
Mandlekar S, Kong A-NT . (2001). Mechanisms of tamoxifen-induced apoptosis. Apoptosis 6: 469–477.
McClay EF, McClay ME, Monroe L, Baron PL, Cole DJ, O'Brien PH et al. (2000). The effect of tamoxifen and cisplatin on the disease-free and overall survival of patients with high risk malignant melanoma. Br J Cancer 83: 16–21.
Nakano H, Nakajima A, Sakon-Komazawa S, Piao JH, Xue X, Okumura K . (2006). Reactive oxygen species mediate crosstalk between NF-kappaB and JNK. Cell Death Differ 13: 730–737.
Nazarewicz RR, Zenebe WJ, Parihar A, Larson SK, Alidema E, Choi J et al. (2007). Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase. Cancer Res 67: 1282–1290.
Osborne CK . (1998). Tamoxifen in the treatment of breast cancer. N Engl J Med 339: 1609–1618.
Suliman A, Lam A, Datta R, Srivastava RK . (2001). Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Oncogene 20: 2122–2133.
Yanamadala V, Negoro H, Gunaratnam L, Kong T, Denker BM . (2007). Galpha 12 stimulates apoptosis in epithelial cells through JNK1 mediated Bcl-2 degradation and upregulation of Ikappa B-alpha. J Biol Chem 282: 24352–24363.
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).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210749
Keywords
This article is cited by
-
Tamoxifen induces eryptosis through calcium accumulation and oxidative stress
Medical Oncology (2023)
-
Anticancer genes (NOXA, PAR-4, TRAIL) are de-regulated in breast cancer patients and can be targeted by using a ribosomal inactivating plant protein (riproximin)
Molecular Biology Reports (2023)
-
Targeting glycolysis by 3-bromopyruvate improves tamoxifen cytotoxicity of breast cancer cell lines
BMC Cancer (2015)
-
Synergistic anticancer effects of a bioactive subfraction of Strobilanthes crispus and tamoxifen on MCF-7 and MDA-MB-231 human breast cancer cell lines
BMC Complementary and Alternative Medicine (2014)
-
“Iron-saturated” bovine lactoferrin improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice
BMC Cancer (2012)