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Corepressors mediate the activation of estrogen receptor α by estrogen and cAMP

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Defense Thèse de doctorat : Univ. Genève, 2016 - Sc. 4915 - 2016/03/23
Abstract The estrogen receptor α (ERα) is a transcription factor that can be directly activated by estrogen or indirectly by other signaling pathways and plays a central role in breast carcinogenesis. We previously reported that activation of the unliganded ERα by cAMP is mediated by phosphorylation of its coactivator CARM1 by protein kinase A (PKA), allowing CARM1 to bind ERα directly. This being insufficient by itself to activate ERα, we looked for additional factors that could be involved in the response of ERα to cAMP. In order to do that we have developed a set of gene knockdown and overexpression experiments in ERα- positive breast cancer cell lines and tested their functional importance for ERα signaling in transactivation assays and for the expression of endogenous ERα target genes in response to cAMP and estrogens. We have investigated the recruitment of these factors to ERα and to chromatin. We have tested different inhibitors of the main catalytic activities of the ERα transcriptional complex to gain insights on their efficacy to disrupt the recruitment of coactivators to ERα and reduce proliferation of breast cancer cells. Finally, we have investigated the expression of certain of these proteins in ERα-positive breast tumors looking for the correlation with the outcome in breast cancer. We identified the histone H3 demethylase LSD1 as a substrate of PKA and an important mediator of this signaling crosstalk as well as of the response to estrogen. Surprisingly, ERα engages not only LSD1, but its partners of the CoREST corepressor complex, the repressor element-1 silencing transcription factor (REST), and the molecular chaperone Hsp90. The recruitment of Hsp90 to promote ERα transcriptional activity suggests that it might be involved as an assembly factor or scaffold. In a breast cancer cell line, which is resistant to the anti-estrogens tamoxifen (OHT) because of constitutively activated PKA, drug combinations partially rescue OHT sensitivity. In ERα-positive breast cancer patients, high expression of the genes encoding some of these factors correlates with poor prognosis. We believe that understanding the molecular mechanisms that trigger activation of ERα by cAMP are important to establish differences or similarities from the estrogen-activated pathway, which might be relevant in the context of breast cancer. Due to the existing correlation of increased PKA activity and OHT resistance in breast cancer the discovery of druggable proteins implicated in the signaling crosstalk of cAMP and ERα might be important in the improvement of the efficacy of endocrine therapy for these tumors.
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URN: urn:nbn:ch:unige-838492
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Research group Groupe Picard
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BENNESCH, Marcela. Corepressors mediate the activation of estrogen receptor α by estrogen and cAMP. Université de Genève. Thèse, 2016. https://archive-ouverte.unige.ch/unige:83849

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Deposited on : 2016-05-25

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