Integrative analysis of gene expression patterns predicts specific modulations of defined cell functions by estrogen and tamoxifen in MCF7 breast cancer cells.

Franck Gadal (1) , Anna Starzec (2) , Christophe Bozic (3) , Céline Pillot-Brochet (3) , Sophie Malinge (3) , V. Ozanne (3) , J. Vicenzi (3) , Laurent Buffat (3) , Gérard Y. Perret (2) , François Iris (4, 5) , Michel Crepin (1)

1 UMR_S_553 - Hemostase, Endothelium, Angiogenese
2 Laboratoire de Pharmacologie Clinique et Expérimentale - Faculté de Médecine
3 Valigen
4 Bio-Modeling Systems
5 Ecole Centrale Paris

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 17beta-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.

Mots clés: GROWTH-FACTOR-BETA; ARYL-HYDROCARBON RECEPTOR; TRANSCRIPTIONAL ACTIVATION; EXTRACELLULAR-MATRIX; EPITHELIAL-CELLS; CARCINOMA-CELLS; DOWN-REGULATION; CDK INHIBITOR; CYCLE ARREST; MECHANISMS

Domaines: Endocrinologie et métabolisme

Franck Gadal, Anna Starzec, Christophe Bozic, Céline Pillot-Brochet, Sophie Malinge, et al.. Integrative analysis of gene expression patterns predicts specific modulations of defined cell functions by estrogen and tamoxifen in MCF7 breast cancer cells.. J Mol Endocrinol, 2005, 34 (1), pp.61-75. ⟨10.1677/jme.1.01631⟩. ⟨hal-00126095⟩