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dc.contributor.advisorGévry, Nicolasfr
dc.contributor.advisorGaudreau, Luc R.fr
dc.contributor.authorSvotelis, Amyfr
dc.date.accessioned2014-05-16T16:04:31Z
dc.date.available2014-05-16T16:04:31Z
dc.date.created2011fr
dc.date.issued2011fr
dc.identifier.isbn9780494833292fr
dc.identifier.urihttp://savoirs.usherbrooke.ca/handle/11143/5166
dc.description.abstractThe human genome is organised into a DNA-protein complex called chromatin, of which the main repeating unit is the nucleosome. Chromatin is generally repressive to gene expression, rendering RNA Polymerase II regulatable gene expression dependent on chromatin remodelling complexes. These complexes will displace nucleosomes or change the nucleosomal structure by incorporating histone variants or by the post- translational modification of histone. Chromatin remodelling works in concert with transcription activators on regulatory elements of regulatable genes. The histone variant H2A.Z has a major role in creating a permissive structure at gene regulatory elements. Conversely, the di- and tri-methylation of histone H3 lysine 27 (H3K27) has a repressive effect on gene regulation, but can be reversed by the recently identified demethylase, JMJD3. The steroid hormone estrogen (E2) and its intracellular receptor estrogen receptor [alpha] (ER[alpha]) stimulate transcription of target genes by promoting local changes in hormone-responsive promoters embedded in chromatin. ER[alpha]-dependent cancers demonstrate deregulated proliferation, and the treatment of these cancers with anti-estrogens (AE) occasionally leads to resistant cancer subtypes. H2A.Z overexpression has been associated with ER[alpha] target gene expression and breast cancer. In addition, an interesting link exists between ER[alpha] and H3K27me3 related chromatin remodelling complexes. We thus hypothesized that ER[alpha]-mediated transcription in normal and antiestrogen-resistant breast cancer implicates the modification of chromatin signatures on target genes and results in proliferation. We observed that H2A.Z overexpression is related to ER[alpha] levels and leads to increased proliferation in low E2 concentrations and in the presence of the AE tamoxifen. We also show that the perturbation of a repressive epigenetic mark that normally controls the expression of the proto-oncogene BCL2 in response to E2 leads to its constitutive transcriptional activation and deregulation of the apoptosis program in AE-resistant breast cancer cells. Therefore my doctoral studies present the following conclusions: (1) epigenetic modifications are useful prognostic markers for breast cancer severity; (2) the deregulation of these modifications leads to carcinogenesis; and (3) continued deregulation of these pathways can lead to more severe breast cancer and AE resistance.fr
dc.language.isoengfr
dc.publisherUniversité de Sherbrookefr
dc.rights© Amy Stovelisfr
dc.subjectModifications d'histonesfr
dc.subjectH2A Zfr
dc.subjectChromatinefr
dc.subjectTranscriptionfr
dc.subjectRéceptor à l'oestrogènefr
dc.titleL'influence du récepteur à l'oestrogène [alpha] sur la dynamique chromatinienne dans les cancers du sein hormono-dépendentsfr
dc.typeThèsefr
tme.degree.disciplineBiologiefr
tme.degree.grantorFaculté des sciencesfr
tme.degree.levelDoctoratfr
tme.degree.namePh.D.fr


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