Estrogen receptor-α-interacting cytokeratins potentiate the antiestrogenic activity of fulvestrant

Xinghua Long, Meiyun Fan, Kenneth P. Nephew

Research output: Contribution to journalArticle

9 Scopus citations


Fulvestrant (ICI 182, 780) is a selective estrogen receptor downregulator (SERD) and potent antiestrogen. In estrogen receptor-alpha-positive ERα(+) breast cancer, the drug immobilizes ERα in the nuclear matrix, inducing receptor polyubiquitination and subsequent degradation via the 26s proteasome. We previously reported that fulvestrant-induced ERα degradation depends on the interaction of ERα with cytokeratins 8 and 18 (CK8/CK18). Here we further investigate the role of these two cytokeratins in the antagonistic activity of the SERD. Using ER-responsive reporter assays, we demonstrate greater antiestrogenic activity of fulvestrant in CK8/CK18(+) vs. CK8/CK18(-) cancer cells and loss of CK8/CK18 expression was observed in a breast cancer cell model for acquired fulvestrant resistance. In contrast, the presence of CK8/CK18 had no effect on the antiestrogenic activity of 4-hydroxytamoxifen, which was unable to induce an interaction between these CKs and ERα. By utilizing the ligand activity inversion ERα mutant L540Q to further examine the mechanism of fulvestrant action, we demonstrate that the ERα mutant does not interact with CK8/CK18 in the presence of fulvestrant and L540Q is not immobilized to the nuclear matrix after antiestrogen treatment. In transcription assays, fulvestrant displayed agonist activity, stimulating L540Q-mediated gene expression. In addition, fulvestrant did not induce an ERβ interaction with CK8/CK18 and subsequent ERβ degradation. Collectively, these results suggest that CK8/18 play an important role in the antiestrogenic action of fulvestrant in breast cancer cells and that these two cytokeratins could serve as prognostic markers for SERD therapy response in breast cancer patients.

Original languageEnglish (US)
Pages (from-to)389-396
Number of pages8
JournalCancer Biology and Therapy
Issue number5
StatePublished - Mar 1 2010


  • Antiestrogen
  • Breast cancer
  • Cytokeratin
  • Estrogen receptor
  • Fulvestrant
  • Tamoxifen

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

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