title: Resistance to antiestrogen arzoxifene is mediated by overexpression of cyclin D1.
abstract: 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 ERalpha-positive breast cancer cells, including tamoxifen-resistant tumors. In this study, we show that overexpression of a regular component of the ERalpha 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 ERalpha in the presence of arzoxifene. In this altered conformation, ERalpha still recruits RNA polymerase II to an estrogen response element-containing promoter, inducing transcription of an ERalpha-dependent reporter gene and of endogenous pS2, and promoting arzoxifene-stimulated growth of MCF-7 cells. Arzoxifene is then converted from an ERalpha antagonist into an agonist. This can be explained by a stabilization of the ERalpha/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 ERalpha upon binding to antiestrogen are at the basis of resistance to antiestrogens.
authors.affiliation: Department of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
authors.forename: Mariska
authors.initials: M
authors.lastname: Rondaij
authors.forename: Kees
authors.initials: K
authors.lastname: Jalink
authors.forename: Z Dave
authors.initials: ZD
authors.lastname: Sharp
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mancini
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.forename: Rob
authors.initials: R
authors.lastname: Michalides
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis*; D004351:Drug Resistance; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal / Q000379:methods; D008956:Models, Chemical; D010880:Piperidines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D010880:Piperidines; D013876:Thiophenes; D019938:Cyclin D1; C115121:LY 353381