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Physiologie autocrine et potentiel oncogénique de l'hormone de croissance

Abstract : Growth hormone (GH) physiological effects are responsible for post-natal body growth through the induction of cell proliferation, metabolism and differentiation. Pituitary GH is released in a pulsatile mode and induces a cellular response adapted to the variations in homeostatic conditions. The signal transduction pathway of GH is shared with the cytokine receptor superfamily and leads to the activation of the Janus Kinase / Signal Transducer and Activator of Transcription (JAK / STAT) proteins. Extrapituitary sites of GH synthesis by endothelial, fibroblastic and epithelial cells have been described and shown to be distinctly regulated from pituitary GH. This ectopic production of GH is released in small concentration, do not contribute to significant elevation of plasma GH and is thought to exert autocrine/paracrine effects.
The main objective of the work presented here was to uncover the physiological role and pathological consequences of autocrine GH using a panel of molecular techniques from the cellular level to animal studies. First, we identified extrapituitary sites of GH expression including organs of the immune system and the mammary gland and evidenced developmentally and physiologically regulated rGH expression. Autocrine GH production by mammary epithelial cells induced their proliferation and counteracted lactogenic differentiation. We also evidenced hGH gene expression in epithelial and fibroblastic cells of the human breast and shown that it was increased in cases of invasive breast cancer. We next established a model of autocrine production of hGH using human mammary carcinoma cells and demonstrated that GH induces a significant activation of cell proliferation and protection against apoptosis. Migratory and invasive capacities of carcinoma cells were also remarkably increased by autocrine hGH and associated with a morphology reminiscent to fibroblastic type and concomitant with the acquisition of epithelial-mesenchymal transition markers. Next, we demonstrated that tumour progression of human mammary carcinoma cells induced by autocrine hGH was associated with the activation of a transcriptional platform involving specific proteins (CHOP, HOXA1, Cyclin D1, c-Myc, Bcl-2, Catalase) which lead to sustained activation of the MAPK pathway as well as mechanisms of cell survival and chemoresistance. We finally demonstrated that forced expression of the hGH gene is sufficient to promote cellular transformation of human mammary epithelial cell as well as in vivo tumour formation suggesting that autocrine GH could act as a human oncoprotein in epithelial cells.
Our work clearly established that GH is an autocrine/paracrine factor physiologically involved in mammary epithelial cell proliferation and pathologically acting as a promoter of tumour progression. Sustained expression of autocrine hGH in human breast epithelial cells result in their oncogenic transformation suggesting the potential use of hGH receptor antagonist as adjunct therapy in human breast cancer.
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Submitted on : Thursday, February 8, 2007 - 3:56:18 PM
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Hichem Claude Mertani. Physiologie autocrine et potentiel oncogénique de l'hormone de croissance. Physiologie [q-bio.TO]. Université Claude Bernard - Lyon I, 2006. ⟨tel-00129746⟩

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