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¹ Unité Inserm U 553, Hôpital St Louis, 75010 Paris, France and Université Paris 13, France
² Laboratoire de Pharmacologie Clinique et Expérimentale, Faculté de Médecine, Université Paris 13, 93017 Bobigny cedex, France
³ Valigen, Tour Neptune, 92086 Paris La Défense, France
⁴ Ecole Centrale de Paris, Grande voie des vignes 92295 Chatenay Malabry, France and Bio-Modeling Systems, 26 Rue St Lambert, Paris 15, France

(Requests for offprints should be addressed to F Gadal; Email: fgadal{at}club-internet.fr)

To explore the mechanisms whereby estrogen and antiestrogen (tamoxifen (TAM)) can regulate breast cancer cell growth, we investigated gene expression changes in MCF7 cells treated with 17ß-estradiol (E₂) and/or with 4-OH-TAM. The patterns of differential expression were determined by the ValiGen Gene IDentification (VGID) process, a subtractive hybridization approach combined with microarray validation screening. Their possible biologic consequences were evaluated by integrative data analysis. Over 1000 cDNA inserts were isolated and subsequently cloned, sequenced and analyzed against nucleotide and protein databases (NT/NR/EST) with BLAST software. We revealed that E₂ induced differential expression of 279 known and 28 unknown sequences, whereas TAM affected the expression of 286 known and 14 unknown sequences. Integrative data analysis singled out a set of 32 differentially expressed genes apparently involved in broad cellular mechanisms. The presence of E₂ modulated the expression patterns of 23 genes involved in anchors and junction remodeling; extracellular matrix (ECM) degradation; cell cycle progression, including G₁/S check point and S-phase regulation; and synthesis of genotoxic metabolites. In tumor cells, these four mechanisms are associated with the acquisition of a motile and invasive phenotype. TAM partly reversed the E₂-induced differential expression patterns and consequently restored most of the biologic functions deregulated by E₂, except the mechanisms associated with cell cycle progression. Furthermore, we found that TAM affects the expression of nine additional genes associated with cytoskeletal remodeling, DNA repair, active estrogen receptor formation and growth factor synthesis, and mitogenic pathways. These modulatory effects of E₂ and TAM upon the gene expression patterns identified here could explain some of the mechanisms associated with the acquisition of a more aggressive phenotype by breast cancer cells, such as E₂-independent growth and TAM resistance.

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