Caracterización de tumores de mama según la expresión de P-Rex1 y análisis in vitro del rol de TGFB2 y los receptores ErbB como posibles activadores de vías de señalización asociados para la progresión del cáncer de mama
Rac1 is a Rho GTPasa widely involved in motility, mitogénesis,\ntransformation and metastasis. P-Rex1 is a Rac1 activator that is overexpressed\nin breast cancer and its silencing inhibits cell migration. P-Rex1\noverexpression is currently associated with luminal tumors. In this work, we\naimed to...
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| Formato: | Tesis de maestría acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2018
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_5918 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_5918.dir/5918.PDF |
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| Sumario: | Rac1 is a Rho GTPasa widely involved in motility, mitogénesis,\ntransformation and metastasis. P-Rex1 is a Rac1 activator that is overexpressed\nin breast cancer and its silencing inhibits cell migration. P-Rex1\noverexpression is currently associated with luminal tumors. In this work, we\naimed to analyze the presence of P-Rex1 in samples from patients from the\nMarie Curie Hospital (Buenos Aires City), and determine its relationship with\nclinical and histopathological parameters. For this purpose, P-Rex1 levels\nwere determined in biopsies, tumors and adjacent tissue from primary\nsurgery in patients not undergoing neoadjuvant therapy. Our analysis\nrevealed high levels of P-Rex1 in both luminal and basal tumors. These\nresults confirm P-Rex1 potential as a therapeutic target not only for the\ntreatment of luminal tumors but also for a certain population of triple negative\npatients.\nHeregulin (HRG) is a ligand for tyrosine-kinase ErbB receptors that\ntriggers Rac1 activation of through P-Rex1 in breast cancer cells. This\nactivation leads to an increase in TGF?2 expression. In fact, the TGF? family\nis involved in cell migration and metastasis. Based on this background, we\naimed to study the dynamics of Rac1 activation by HRG and determine\nTGF?2 ability to induce migration and to interact with ErbB receptors in\nbreast cancer cell lines. Measurements of activated-Rac1 by pull down\nassays, measurement of mRNA by quantitative PCR and assessment of\nmigration by wound healing assays were performed. We conclude that HRG\nis necessary for the initial activation of Rac. Subsequently, breast cancer\ncells begin producing autocrine factors that are necessary for maintenance of\nHRG-initiated Rac1 activation. In addition, we show that HRG induces an\nincrease in mRNA of TGF?2 in a time-dependent manner. Moreover, the\nwound healing assays revealed that TGF?2 itself induces migration of breast\ncancer cells in a dose-dependent manner and that the combined addition of\nHRG and TGF?2 produces the same increase in cell migration as HRG\nalone. These results suggest that there is a sequential relationship between\nthe peak of Rac1 activation and the maximum increase of TGF?2. We\npropose that this cytokine is necessary for the maintenance of the phenotype\ntriggered by HRG in breast cancer cells.\nThe results obtained as a whole will contribute to establishing the\nprognostic and therapeutic value of P-Rex1 and the elucidation of relevant\nsignaling pathways for tumor progression. The determination of a cross\nsignaling between TGF?2 and HRG could contribute to the search for\nalternative therapies for breast cancer patients. |
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