title: Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells.
abstract: Antiestrogens used for breast cancer (BC) treatment differ among each other for the ability to affect estrogen receptor (ER) activity and thereby inhibit hormone-responsive cell functions and viability. We used high-density cDNA microarrays for a comprehensive definition of the gene pathways affected by 17beta-estradiol (E2), ICI 182,780 (ICI), 4OH-tamoxifen (Tamoxifen), and raloxifene (RAL) in ER-positive ZR-75.1 cells, a suitable model to investigate estrogen and antiestrogen actions in hormone-responsive BC. The expression of 601 genes was significantly affected by E2 in these cells; in silico analysis reveals that 86 among them include one or more potential ER binding site within or near the promoter and that the binding site signatures for E2F-1, NF-Y, and NRF-1 transcription factors are significantly enriched in the promoters of genes induced by estrogen treatment, while those for CAC-binding protein and LF-A1 in those repressed by the hormone, pointing to novel transcriptional effectors of secondary responses to estrogen in BC cells. Interestingly, expression of 176 E2-regulated mRNAs was unaffected by any of the antiestrogens tested, despite the fact that under the same conditions the transcriptional and cell cycle stimulatory activities of ER were inhibited. On the other hand, of 373 antiestrogen-responsive genes identified here, 52 were unresponsive to estrogen and 25% responded specifically to only one of the compounds tested, revealing non-overlapping and clearly distinguishable effects of the different antiestrogens in BC cells. As some of these differences reflect specificities of the mechanism of action of the antiestrogens tested, we propose to exploit this gene set for characterization of novel hormonal antagonists and selective estrogen receptor modulators (SERMs) and as a tool for testing new associations of antiestrogens, more effective against BC.
authors.affiliation: Dipartimento di Patologia generale, Seconda Università degli Studi di Napoli, Vico L. De Crecchio 7, 80138 Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Scafoglio
authors.forename: Concetta
authors.initials: C
authors.lastname: Ambrosino
authors.forename: Luigi
authors.initials: L
authors.lastname: Cicatiello
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Mario
authors.initials: M
authors.lastname: Ardovino
authors.forename: Paola
authors.initials: P
authors.lastname: Bontempo
authors.forename: Nicola
authors.initials: N
authors.lastname: Medici
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Molinari
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Angelo
authors.initials: A
authors.lastname: Facchiano
authors.forename: Raffaele A
authors.initials: RA
authors.lastname: Calogero
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.forename: Nadia
authors.initials: N
authors.lastname: Menini
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ponzone
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Biglia
authors.forename: Piero
authors.initials: P
authors.lastname: Sismondi
authors.forename: Michele
authors.initials: M
authors.lastname: De Bortoli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Weisz
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D019295:Computational Biology; D018076:DNA, Complementary / Q000235:genetics; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D018076:DNA, Complementary; D004965:Estrogen Antagonists; D004967:Estrogens