Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

Clin Cancer Res. 2018 May 15;24(10):2452-2463. doi: 10.1158/1078-0432.CCR-17-1381. Epub 2018 Jan 23.


Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452-63. ©2018 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Protein Processing, Post-Translational*
  • Receptors, Estrogen / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Hormonal
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Receptors, Estrogen
  • TNF-Related Apoptosis-Inducing Ligand