title: Interference with ER-α enhances the therapeutic efficacy of the selective CDK inhibitor roscovitine towards ER-positive breast cancer cells.
abstract: In recent years many risk factors for the development of breast cancer that are linked to estrogens have been identified, and roscovitine (ROSC), a selective cyclin-dependent kinase (CDK) inhibitor, has been shown to be an efficient inhibitor of the proliferation of human breast cancer cells. Therefore, we have examined the possibility that interference with estrogen signaling pathways, using tamoxifen (TAM), a selective estrogen receptor modulator (SERM), could modulate the efficacy of treatment with ROSC. In conjunction with TAM, ROSC exhibited enhanced anti-proliferative activity and CDK inhibition, particularly in estrogen-dependent MCF-7 cells. The interaction between both drugs was synergistic. However, in ER-α-negative cells the interaction was antagonistic. Exposure of MCF-7 cells to ROSC abolished the activating phosphorylation of CDK2 and CDK7 at Ser(164/170). This in turn prevented the phosphorylation of the carboxyl-terminal repeat domain of RNA Polymerase II and ER-α at Ser(118), resulting in the down-regulation of the latter. Concomitantly, wt p53 was strongly activated by phosphorylation at Ser(46). Our results demonstrate that ROSC negatively affects the functional status of ER-α, making it potentially useful in the treatment of estrogen-dependent breast cancer cells.
authors.affiliation: Cell Cycle Regulation Group, Institute of Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. jozefa.gadek-wesierski@meduniwien.ac.at
authors.forename: Józefa
authors.initials: J
authors.lastname: Węsierska-Gądek
authors.forename: David
authors.initials: D
authors.lastname: Gritsch
authors.forename: Nora
authors.initials: N
authors.lastname: Zulehner
authors.forename: Oxana
authors.initials: O
authors.lastname: Komina
authors.forename: Margarita
authors.initials: M
authors.lastname: Maurer
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D047628:Estrogen Receptor alpha; D047428:Protein Kinase Inhibitors; D011687:Purines; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000077546:Roscovitine; D012694:Serine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human