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首页> 外文学位 >Role de la synthese de l'acide retinoique dans le controle de la proliferation et de la differenciation des cellules epitheliales mammaires.
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Role de la synthese de l'acide retinoique dans le controle de la proliferation et de la differenciation des cellules epitheliales mammaires.

机译：视黄酸的合成在控制乳腺上皮细胞增殖和分化中的作用。

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摘要

Retinoic acid (RA) is ligand of nuclear receptors RARs and RXRs that act as ligand-inducible transcription factors and mediate its biological effects. It was shown that RA has antiproliferative and prodifferenciating properties in mammary cells. A loss of RA sensitivity was associated with increased tumorigenicity in the mammary tissue, potentially facilitating the growth of tumors. It's believed that is was mainly due to deficiencies in the RA signaling pathway, probably caused by the loss of RAR and RXR expressions. However, some tumorigenic cell lines were still reported to be RA sensitive.;Keywords: retinoid acid, RALDH, breast cancer, stem cell;The role of RA synthesis in mammary tumorigenesis has been poorly characterized. RA is synthezised in target tissues from vitamin A (retinol) its precursor in blood. It was shown that mammary epithelial cells were able to synthesize RA from retinol in vitro. We show here for the first time that RALDH3, an enzyme involved in RA synthesis, is probably responsible for RA synthesis in normal mammary epithelial cells. Our result suggest that luminal cancer cells (that express ERalpha and represent 75 % of breast tumors) have a very low capacity of RA synthesis, probably due to a low estrogen-mediated RALDH3 expression. It might represent a new mechanism of estrogen-driven tumorigenenesis allowing RA sensitive tumors to proliferate in the presence of retinol in the blood. It was suggested that RALDH1, an other enzyme of the RA synthesis pathway that shares 70 % of identity with RALDH3, is a marker of mammary stem cells, of more aggressive tumors and higher occurance of metastasis. We shown that unlinke RALDH1, RALDH3 is a marker of a lower occurance of metastasis and probably a marker of differentiation, suggesting different roles in the mammary gland for these 2 enzymes. This is in good agreement with our results showing that they have very different enzymatic properties. All together our data suggest that RALDH1 and 3 might be markers of different populations of cells of in the mammary epithelium. We propose to use the differences between RALDH1 and 3 to rationally develop methods and tools to separate and isolate RALDH1- and 3-expressing cells that would help the understand the role of RA synthesis in the mammary gland
机译：维甲酸（RA）是核受体RAR和RXR的配体，它们充当配体诱导型转录因子并介导其生物学作用。结果表明，RA在乳腺细胞中具有抗增殖和增生特性。 RA敏感性的丧失与乳腺组织的致瘤性增加有关，潜在地促进了肿瘤的生长。据认为，这主要是由于RA信号通路的缺陷所致，可能是RAR和RXR表达的缺失所致。然而，仍然有一些致瘤细胞系对RA敏感。关键词：类维生素A酸，RALDH，乳腺癌，干细胞； RA合成在乳腺肿瘤发生中的作用尚不明确。 RA是由血液中的前体维生素A（视黄醇）在靶组织中合成的。结果表明，乳腺上皮细胞能够在体外从视黄醇合成RA。我们首次在这里显示RALDH3（一种参与RA合成的酶）可能是正常乳腺上皮细胞中RA合成的原因。我们的结果表明，腔内癌细胞（表达ERalpha并代表75％的乳腺肿瘤）具有非常低的RA合成能力，这可能是由于雌激素介导的RALDH3表达低所致。它可能代表了雌激素驱动的肿瘤发生的新机制，使RA敏感肿瘤在血液中存在视黄醇的情况下增殖。有人提出，RALDH1是RA合成途径的另一种酶，与RALDH3具有70％的同一性，是乳腺干细胞，更具侵袭性的肿瘤和更高的转移发生率的标志。我们显示，未连接的RALDH1，RALDH3是转移发生率较低的标志，并且可能是分化的标志，表明这两种酶在乳腺中的作用不同。这与我们的结果非常吻合，表明它们具有非常不同的酶促性质。所有我们的数据共同表明，RALDH1和3可能是乳腺上皮细胞不同种群的标志物。我们建议利用RALDH1和3之间的差异来合理开发分离和分离表达RALDH1和3的细胞的方法和工具，这有助于理解RA合成在乳腺中的作用

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  • 作者

    Parisotto, Maxime.;

  • 作者单位

    Universite de Montreal (Canada).;

  • 授予单位 Universite de Montreal (Canada).;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 254 p.
  • 总页数 254
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

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