Survivin plays as a resistant factor against tamoxifen-induced apoptosis in human breast cancer cells

Breast Cancer Res Treat. 2009 Sep;117(2):261-71. doi: 10.1007/s10549-008-0164-5. Epub 2008 Sep 25.

Abstract

Tamoxifen has been the mainstay of endocrine therapy for estrogen receptor-positive breast cancer. However, approximately 40% of breast cancer patients do not respond to tamoxifen treatment. Further, most tumors eventually acquire tamoxifen resistance. Therefore, it is necessary to develop effective modalities to enhance the efficacy of tamoxifen in breast cancer treatment. In this study, we investigated the mechanism by which breast cancer cells develop resistance against tamoxifen from the viewpoint of tamoxifen-induced apoptosis. Overexpression of the anti-apoptotic molecule survivin rendered the human breast cancer cells MCF-7 resistant to tamoxifen-induced apoptosis. To examine whether the down-regulation of survivin can enhance tamoxifen-induced apoptosis, we introduced siRNA targeting the survivin gene (survivin-siRNA) into MCF-7 cells. Survivin-siRNA transfection not only induced apoptosis without tamoxifen treatment but also augmented the tamoxifen-induced apoptosis. We have previously demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs), which are widely used to reduce the serum cholesterol levels in hypercholesterolemia patients, decreases survivin expression in colon cancer cells. To develop a pharmacological approach for improving the efficacy of tamoxifen treatment, we determined whether HRIs can enhance tamoxifen-induced apoptosis. Lovastatin, an HRI, down-regulated the expression of survivin protein in MCF-7 cells in a dose-dependent manner. In addition, the proportion of apoptotic cells induced by the tamoxifen and lovastatin combination was greater than the theoretical additive effect. These results suggest that survivin may function as a factor inducing resistance against tamoxifen-induced apoptosis, and the combined use of tamoxifen and HRI may be a novel approach to overcome tamoxifen resistance in breast cancer.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • RNA, Messenger / analysis
  • RNA, Small Interfering
  • Survivin
  • Tamoxifen / pharmacology
  • Transfection

Substances

  • BIRC5 protein, human
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Survivin
  • Tamoxifen