title: Centrosome aberrations in human mammary epithelial cells driven by cooperative interactions between p16INK4a deficiency and telomere-dependent genotoxic stress.
abstract: Virtually all human cancers display chromosome instability (CIN), a condition in which chromosomes are gained or lost at a high rate. CIN occurs early in cancer development where it may undermine the advance of the neoplastic disease. With the aim of establishing the mechanisms underlying CIN in cancer, we investigated possible links between telomere-dysfunction and centrosome defects, which were seen to coincide in early in breast carcinogenesis using human mammary epithelial cells (HMECs). In this study, we show that TP53 proficient vHMECs cells develop centrosome aberrations when telomere-dysfunction genotoxic stress is produced in the presence of a defective p16INK4a setting and in parallel with an activation of the DNA damage checkpoint response. These aberrations consist of the accumulation of centrosomes in polyploid vHMECs, plus centriole overduplication in both diploid and polyploid cells, thus reflecting that distinct mechanisms underlie the generation of centrosome aberrations in vHMECs. Transduction of vHMEC with hTERT, which rescued the telomere dysfunction phenotype and consequently reduced DNA damage checkpoint activation, led to a progressive reduction of centrosome aberrations with cell culture, both in diploid and in polyploid vHMECs. Radiation-induced DNA damage also raised centrosome aberrations in vHMEC-hTERT. Collectively, our results, using vHMECs define a model where p16INK4a deficiency along with short dysfunctional telomeres cooperatively engenders centrosome abnormalities before p53 function is compromised.
authors: Cell Biology Unit, Department of Cell Biology, Physiology and Immunology, Bioscience School, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Daniel
authors: D
authors: Domínguez
authors: Cell Biology Unit, Department of Cell Biology, Physiology and Immunology, Bioscience School, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Purificación
authors: P
authors: Feijoo
authors: Cell Biology Unit, Department of Cell Biology, Physiology and Immunology, Bioscience School, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Aina
authors: A
authors: Bernal
authors: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
authors: Amaia
authors: A
authors: Ercilla
authors: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
authors: Neus
authors: N
authors: Agell
authors: Cell Biology Unit, Department of Cell Biology, Physiology and Immunology, Bioscience School, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Anna
authors: A
authors: Genescà
authors: Cell Biology Unit, Department of Cell Biology, Physiology and Immunology, Bioscience School, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Laura
authors: L
authors: Tusell
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D002502:Centrioles / Q000235:genetics / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D042361:Mammary Glands, Human / Q000166:cytology; D008856:Microscopy, Fluorescence; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D057891:Tetraploidy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; D019098:Telomerase
keywords: CDKN2A; centrosome aberrations; human mammary epithelial cells; telomere dysfunction