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CNRS UMR 5160, Faculté de Pharmacie, 15 Av Charles Flahault, BP 14491, 34093 Montpellier Cedex 5, France
¹ Laboratoire d’Oncogenetique-INSERM E0017, Centre René Huguenin, 92210 St-Cloud, France
² INSERM U540, 70 Rue de Navacelles, 34090 Montpellier, France
³ Laboratoire TAGC, CIML, Université d’Aix-Marseille II, 13288 Marseille Cedex 9, France

(Requests for offprints should be addressed to PA Cohen; Email: pascale.cohen{at}ibph.pharma.univ-montp1.fr)

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 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.

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