title: Cell cycle dependent oscillatory expression of estrogen receptor-α links Pol II elongation to neoplastic transformation.
abstract: Decades of studies provided a detailed view of the mechanism of estrogen receptor-α (ERα) regulated gene transcription and the physio-pathological relevance of the genetic programs controlled by this receptor in a variety of tissues. However, still limited is our knowledge on the regulation of ERα synthesis. Preliminary observations showed that the expression of ERα is cell cycle regulated. Here, we have demonstrated that a well described polymorphic sequence in the first intron of ERα (PvuII and XbaI) has a key role in regulating the ERα content in cycling cells. We have shown that the RNA Pol II (Pol II) elongation is blocked at the polymorphic site and that the proto-oncogene c-MYB modulates the release of the pausing polymerase. It is well known that the two SNPs are associated to an increased risk, progression, survival and mortality of endocrine-related cancers, here we have demonstrated that the c-MYB-dependent release of Pol II at a specific phase of the cell cycle is facilitated by the px haplotype, thus leading to a higher ERα mitogenic signal. In breast cancer, this mechanism is disrupted when the hormone refractory phenotype is established; therefore, we propose this oscillator as a novel target for the development of therapies aimed at sensitizing breast cancer resistant to hormonal treatments. Because PvuII and XbaI were associated to a broad range physio-pathological conditions beside neoplastic transformation, we expect that the ERα oscillator contributes to the regulation of the estrogen signal in several tissues.
authors: Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy;
authors: Cristina
authors: C
authors: Vantaggiato
authors: Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy;
authors: Marta
authors: M
authors: Tocchetti
authors: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; and.
authors: Vera
authors: V
authors: Cappelletti
authors: Experimental Oncology Department, Istituto Regina Elena, 00158 Rome, Italy.
authors: Aymone
authors: A
authors: Gurtner
authors: Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy;
authors: Alessandro
authors: A
authors: Villa
authors: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; and.
authors: Maria Grazia
authors: MG
authors: Daidone
authors: Experimental Oncology Department, Istituto Regina Elena, 00158 Rome, Italy.
authors: Giulia
authors: G
authors: Piaggio
authors: Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy;
authors: Adriana
authors: A
authors: Maggi
authors: Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy; paolo.ciana@unimi.it.
authors: Paolo
authors: P
authors: Ciana
mesh_terms: D000704:Analysis of Variance; D002453:Cell Cycle / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D006801:Humans; D061986:MCF-7 Cells; D010957:Plasmids / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D012319:RNA Polymerase II / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012319:RNA Polymerase II
keywords: genetic polymorphisms; oscillatory gene expression; polymerase blockage; steroid receptors; transcriptional oscillators