title: Molecular changes associated with the agonist activity of hydroxy-tamoxifen and the hyper-response to estradiol in hydroxy-tamoxifen-resistant breast cancer cell lines.
abstract: The aim of this study was to explore the pharmacological response to 4-hydroxy-tamoxifen (OH-Tam) and to estradiol (E2) in three cell lines: MVLN, a human breast carcinoma cell line derived from MCF-7, and two MVLN-derived OH-Tam-resistant (OTR) cell lines, called CL6.8 and CL6.32. The OH-Tam response in the OTR cells was associated with the development of both an agonist activity of the drug on cell proliferation and the resistance of the cells to OH-Tam-induced apoptosis. The OTR cells also developed an increased sensitivity to the E2 growth-stimulating activity. To delineate the genes that determine such responses, we combined a mini-array-based gene-selection approach and an extensive real-time quantitative PCR exploration in the MVLN and OTR cell lines exposed to three pharmacological conditions: a 4-day treatment with E2, OH-Tam or both E2 and OH-Tam. Compiled data revealed a hyper-response to E2 and a modification of the OH-Tam pharmacological response (loss of antagonist action and agonist activity) at the gene-expression level. The proteins encoded by the genes selected in this study have been reported to be involved in the regulation of cell proliferation, cell transformation, DNA repair and apoptosis, or belong to the ErbB/epidermal growth factor receptor-driven pathway. Our data also provide evidence of changes in transcriptional co-regulator expression, elevated mitogen-activated protein kinase activity and increase in the phosphorylation status of estrogen receptor alpha on serine residue 118 in the OTR cell lines, suggesting the possible involvement of such mechanisms in the agonist activity of OH-Tam and/or the hyper-response of cells to E2. Taken together, our study should enhance our knowledge of the multifactorial events associated with the development of Tam resistance in two independent cell lines issued from the same selection process and should help in the identification of potential molecular targets for diagnosis or therapy.
authors.affiliation: CNRS UMR 5160, Faculté de Pharmacie, 15 Av Charles Flahault, BP 14491, 34093 Montpellier Cedex 5, France.
authors.forename: J A
authors.initials: JA
authors.lastname: Vendrell
authors.forename: I
authors.initials: I
authors.lastname: Bieche
authors.forename: C
authors.initials: C
authors.lastname: Desmetz
authors.forename: E
authors.initials: E
authors.lastname: Badia
authors.forename: S
authors.initials: S
authors.lastname: Tozlu
authors.forename: C
authors.initials: C
authors.lastname: Nguyen
authors.forename: J C
authors.initials: JC
authors.lastname: Nicolas
authors.forename: R
authors.initials: R
authors.lastname: Lidereau
authors.forename: P A
authors.initials: PA
authors.lastname: Cohen
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000819:agonists / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000627:therapeutic use*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D013629:Tamoxifen / Q000819:agonists / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol