title: Development of cross-resistance to tamoxifen in raloxifene-treated breast carcinoma cells.
abstract: Selective estrogen receptor modifiers (SERMs) are used chronically in the treatment of breast cancer and osteoporosis but some patients become resistant, at which point second-line SERMs are considered as options. Because the use of SERMs is increasing and breast cancer is so common, we tested the hypothesis that treatment with SERMs can induce cross-resistance to other SERMs. We used three cultured breast carcinoma cell lines (MCF-7, ZR-75-1, and T47D) which are estrogen-receptor-positive (ER+) and are prone to developing resistance to hormonal treatment. Cell lines were exposed to increasing doses of raloxifene. Raloxifene-resistant clones were selected and tested for cross-resistance to tamoxifen. Compared to untreated cells, raloxifene-resistant clones showed an increased IC50 (reduced potency) of about 15,000-fold with no apparent change in maximal inhibition of cell growth. These same raloxifene-resistant clones were also about 15-fold more resistant to the growth-inhibiting effects of tamoxifen. While the resistance to tamoxifen is considerably less marked (1000-fold less), it is large enough to raise the question as to whether patients who become resistant to raloxifene will benefit by switching to tamoxifen or vice versa.
authors.affiliation: Division of Genetic and Preventive Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Z O
authors.initials: ZO
authors.lastname: Gao
authors.forename: Z P
authors.initials: ZP
authors.lastname: Gao
authors.forename: J Z
authors.initials: JZ
authors.lastname: Fields
authors.forename: B M
authors.initials: BM
authors.lastname: Boman
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride