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Resistance to Antiestrogen Arzoxifene Is Mediated by Overexpression of Cyclin D1

Departments of Cell Biology (W.Z., M.R., J.N., R.M., K.J.), The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; The University of Texas Institute for Biotechnology (Z.D.S.), San Antonio, Texas 78245; and Department of Molecular & Cellular Biology (M.A.M.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. R. Michalides, Department of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: r.michalides{at}nki.nl.

Resistance to tamoxifen treatment occurs in approximately 50% of the estrogen receptor (ER)-positive breast cancer patients. Resistant patients would benefit from treatment with other available antiestrogens. Arzoxifene is an effective growth inhibitor of ER-positive breast cancer cells, including tamoxifen-resistant tumors. In this study, we show that overexpression of a regular component of the ER 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 ER in the presence of arzoxifene. In this altered conformation, ER still recruits RNA polymerase II to an estrogen response element-containing promoter, inducing transcription of an ER-dependent reporter gene and of endogenous pS2, and promoting arzoxifene-stimulated growth of MCF-7 cells. Arzoxifene is then converted from an ER antagonist into an agonist. This can be explained by a stabilization of the ER/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 ER upon binding to antiestrogen are at the basis of resistance to antiestrogens.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   Cyclin D1  |  SRC-1

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen  |  Fulvestrant