Resistance to antiestrogen arzoxifene is mediated by overexpression of cyclin D1

Wilbert Zwart, Mariska Rondaij, Kees Jalink, Z. Dave Sharp, Michael A. Mancini, Jacques Neefjes, Rob Michalides

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Resistance to tamoxifen treatment occurs in approximately 50% of the estrogen receptor (ER)α-positive breast cancer patients. Resistant patients would benefit from treatment with other available antiestrogens. Arzoxifene is an effective growth inhibitor of ERα-positive breast cancer cells, including tamoxifen-resistant tumors. In this study, we show that overexpression of a regular component of the ERα transcription factor complex, cyclin D1, which occurs in approximately 40% of breast cancer patients, renders cells resistant to the new promising antiestrogen, arzoxifene. Overexpression of cyclin D1 alters the conformation of ERα in the presence of arzoxifene. In this altered conformation, ERα still recruits RNA polymerase II to an estrogen response element-containing promoter, inducing transcription of an ERα-dependent reporter gene and of endogenous pS2, and promoting arzoxifene-stimulated growth of MCF-7 cells. Arzoxifene is then converted from an ERα antagonist into an agonist. This can be explained by a stabilization of the ERα/steroid receptor coactivator-1 complex in the presence of arzoxifene, only when cyclin D1 is overexpressed. These results indicate that subtle changes in the conformation of ERα upon binding to antiestrogen are at the basis of resistance to antiestrogens.

Original languageEnglish (US)
Pages (from-to)1335-1345
Number of pages11
JournalMolecular Endocrinology
Volume23
Issue number9
DOIs
StatePublished - Sep 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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