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Cancer de la prostate et mécanismes de résistance à la castration : étude du rôle des récepteurs nucléaires LXR

Abstract : Androgen deprivation therapy remains the gold standard treatment for advanced prostate cancer. Unfortunately, most of the patients who initially respond to androgen deprivation therapy, later experience tumor relapse, which inevitably progresses to a lethal pathology, named castration-resistant prostate cancer (CRPC).Lipid metabolism anomalies are a key feature of prostate tumor cells. Among these, prostate tumors present excessive cholesterol accumulation. Consistently, epidemiologic studies associate high level of cholesterol with an increased risk of prostate cancer and advanced pathology. LXR nuclear receptors are key regulators of intracellular cholesterol homeostasis that are also implicated in immune physiology through regulation of inflammatory processes. Previous studies conducted in our lab also demonstrated the anti-proliferative and pro-apoptotic effects of LXR in prostate cancer, suggesting a potential central role of these nuclear receptors in this disease.In this context, the goal of my work was to study the role of nuclear receptors LXR in prostate cancer and especially in response to castration. My results show that in response to castration, LXR knockout mice present chronic inflammation of the prostate that eventually induces development of neoplasia. In a Pten-null tumor mouse model, LXR deletion exacerbates inflammation and results in a concomitant increase in proliferation of the prostate. However, this has no significant impact on tumor aggressiveness. To bypass the role of LXR in tumor microenvironment, and especially in the control of immune response to castration, we developed and studied the phenotype mice with conditional ablation of LXR restricted to prostate epithelium. Preliminary analyses did not show a significant phenotype in the prostate of these mice, suggesting that most of the effects of LXR ablation in the prostate result from its activity in the microenvironment.Altogether, these results demonstrate that LXR nuclear receptors, by regulating inflammation in response to castration, can favor epithelial tumor initiation and increase proliferation of the prostate.
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Submitted on : Thursday, February 4, 2021 - 7:40:17 PM
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Laura Bousset. Cancer de la prostate et mécanismes de résistance à la castration : étude du rôle des récepteurs nucléaires LXR. Génétique. Université Clermont Auvergne, 2019. Français. ⟨NNT : 2019CLFAS016⟩. ⟨tel-03132200⟩

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