Resistance to Antiestrogen Arzoxifene Is Mediated by Overexpression of Cyclin D1

Resistance to tamoxifen treatment occurs in approximately 50% of the estrogen receptor ( ER)alpha-positive breast cancer patients. Resistant patients would benefit from treatment with other available antiestrogens. Arzoxifene is an effective growth inhibitor of ER alpha-positive breast cancer cells, including tamoxifen-resistant tumors. In this study, we show that overexpression of a regular component of the ER alpha 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 alpha in the presence of arzoxifene. In this altered conformation, ER alpha still recruits RNA polymerase II to an estrogen response element-containing promoter, inducing transcription of an ER alpha-dependent reporter gene and of endogenous pS2, and promoting arzoxifene-stimulated growth of MCF-7 cells. Arzoxifene is then converted from an ER alpha antagonist into an agonist. This can be explained by a stabilization of the ER alpha/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 alpha upon binding to antiestrogen are at the basis of resistance to antiestrogens. (Molecular Endocrinology 23: 1335-1345, 2009)