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Etude du rôle du facteur de transcription Pea3 pendant la morphogenèse et la tumorigenèse mammaires : caractérisation de ses propriétés pro-morphogènes et pro-tumorigènes : étude des mécanismes moléculaires associés

Abstract : "Proteins of the PEA3 group (Pea3, Erm and Er81) belong to the ETS family of transcription factors. They are expressed in organs that undergo an epithelial branching morphogenesis process such as the lungs and the mammary gland. Moreover, in these organs, they are aberrantly expressed during cancer progression. Indeed, during breast cancer high Pea3 or Erm expression is respectively associated with cancer metastatic potential and a lower patient survival rate. Finally, as transcription factors they control the expression of specific genes called target genes. Even though some of these genes are known, more work is needed to understand the molecular mechanism governed by the PEA3 transcription factors. The main topic of my PhD is the study of the role of the Pea3 transcription factor during mammary morphogenesis and tumorigenesis using two complementary approaches: 1- characterize the morphogenetic properties that are controlled by Pea3 during the mammary morphogenesis and tumorigenesis events 2- find and characterize the genes that are regulated by Pea3 using a large scale transcriptomic analysis based on a microarray technology. The strategy is based on the utilization of two main cell lines in which we modulate Pea3 expression: an epithelial cell line, model of mammary morphogenesis (TAC 2.1) in which we overexpress Pea3 and a cancer cell line, model of mammary tumorigenesis (MMT) in which Pea3 expression is knocked down by means of small interfering RNA sequences. During my PhD we showed that Pea3 controls the proliferation, invasion and migration properties of TAC 2.1 and MMT cells. In agreement with these data, the transcriptomic analysis after Pea3 expression modulation in these cells (overexpression or knockdown) demonstrate that a large proportion of the Pea3 regulated genes are already known players in the regulation of the proliferation, invasion and migration processes. Amongst these genes, we focused on the cyclin d2 gene which is a well characterized actor in cell cycle progression and cell proliferation. We showed that cyclin d2 is direct Pea3 target gene. The cyclin d2 gene gives rise to two different isoforms generated by a splicing event (Cyclin D2 and Cyclin D2 Trc) that are both regulated by Pea3 at the mRNA and protein levels. We then evaluated the function of these two isoforms in the mammary epithelial cell line TAC 2.1. Overexpression of these proteins in the TAC2.1 cells leads to a modification, in an opposite fashion, of their ability to grow and organize in 3D structures within a collagen envirronement. The Cyclin D2 and the Cyclin D2 Trc respectively repressing and enhancing these abilities. The use of small interfering RNA sequences targeting specifically one or the other isoform allowed us to show a functional link between both isoforms and the Pea3 transcription factor , again in an opposite way, especially during cell cycle progression and during epithelial to mesenchymal conversion, a hallmark of development and cancer progression. Thus, this study gives new clues to understand the involvement of the Pea3 transcription factor during mammary morphogenesis and tumorigenesis, events in which the cyclin d2 gene seems to be a major player. The characterization of the molecular events governed by Pea3 should help in defining new therapeutic strategies against breast cancer progression. "
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https://tel.archives-ouvertes.fr/tel-00605540
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Submitted on : Saturday, July 2, 2011 - 1:19:10 AM
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Franck Ladam. Etude du rôle du facteur de transcription Pea3 pendant la morphogenèse et la tumorigenèse mammaires : caractérisation de ses propriétés pro-morphogènes et pro-tumorigènes : étude des mécanismes moléculaires associés. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2010. Français. ⟨NNT : 2010LIL2S031⟩. ⟨tel-00605540⟩

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