title: Clusterin: a potential target for improving response to antiestrogens.
abstract: Antiestrogens represent the first line of therapy in the treatment of estrogen receptor-positive (ER+) breast cancer patients. Unfortunately, up to 40% of patients develop resistance associated with progression and frequently die for metastatic breast cancer. The molecular events leading to pharmacological resistance are not completely understood. We attempted to verify in an experimental model the role of cytoplasmic clusterin (CLU), a cytoprotective protein found to be up-regulated in antiestrogen-resistant patients, following neoadjuvant treatment with toremifene. The role of cytoplasmic clusterin in modulating response to two antiestrogens (toremifene and tamoxifen) was studied in two ER+ anti-estrogen-sensitive cell lines (MCF-7, 734B) and one ER+ antiestrogen-resistant cell line (T47D) using siRNA strategy. Resistant cells were characterised by higher levels of cytoplasmic clusterin than sensitive cells, and antiestrogen treatments up-regulated clusterin levels in both sensitive and resistant cell lines. Treatment with siRNA completely abolished cytoplasmic clusterin expression in all cell lines, but its down-regulation resulted in a significant decrease of cell growth only in the resistant line. We therefore concluded that: i) basal clusterin levels are higher in antiestrogen resistant cells, ii) clusterin is up-regulated following antiestrogen treatment independently of the sensitivity of the cell line, iii) down-regulation of cytoplasmic clusterin restores sensitivity to toremifene in the antiestrogen-resistant cell line. Such results support the concept that targeting CLU could represent a promising therapeutic strategy in association with antiestrogen treatment in breast cancer patients.
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, I-20133 Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Toffanin
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Daidone
authors.forename: Patrizia
authors.initials: P
authors.lastname: Miodini
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.forename: Paolo
authors.initials: P
authors.lastname: Gandellini
authors.forename: Vera
authors.initials: V
authors.lastname: Cappelletti
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051152:Clusterin / Q000737:chemistry / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008495:Medical Oncology / Q000379:methods; D008954:Models, Biological; D009362:Neoplasm Metastasis; D013629:Tamoxifen / Q000494:pharmacology; D017312:Toremifene / Q000494:pharmacology
chemical_list: D051152:Clusterin; D020847:Estrogen Receptor Modulators; D013629:Tamoxifen; D017312:Toremifene