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Heregulin (HRG) and type I receptor tyrosine kinase (RTK) expression was investigated in the highly invasive and metastatic LM3 cell line, our previously described model of metastasis for mammary cancer (Bal de Kier Joffe et al. [1986] Invasion Metastasis 6:302-12; Urtreger et al. [1997] Int J Oncol 11:489-96). Although LM3 cells do not express HRG, they exhibit high levels of ErbB-2 and ErbB-3 as well as moderate expression of ErbB-4. Addition of exogenous HRGβ1 resulted in inhibition of both proliferation and migration of LM3 cells. HRGβ1 was also able to decrease the activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9), 2 key enzymes in the invasion and metastatic cascade. HRGβ1 treatment of LM3 cells induced tyrosine phosphorylation of ErbB-2, ErbB-3 and ErbB-4 as well as the formation of ErbB-2/ErbB-3 and ErbB-2/ErbB-4 heterodimers. Assessment of the signaling pathways involved in HRGβ1 action indicated that the addition of HRGβ1 to LM3 cells resulted in activation of phosphatidylinositol 3-kinase (PI-3K) and in strong induction of the association of the p85 subunit of PI-3K with ErbB-3. HRGβ1 also caused the rapid activation of ERKI/ERK2 and Stat3 and Stat5 (signal transducers and activators of transcription [STAT]). This is the first demonstration of the ability of HRGβ1 to activate STATs in mammary tumor cells. Blockage of PI-3K activity with its chemical inhibitor wortmannin, or of MEKI/ERKs activity with PD98059, resulted in suppression of the ability of HRGβ1 to inhibit LM3 cell growth. Notwithstanding the suppression of these 2 signaling pathways, HRGβ1 still proved capable of inhibiting uPA activity. Therefore, our results provide evidence that signaling pathways involved in HRGβ1-induced proliferation appear to be distinct from those involved in HRGβ1 regulation of uPA, a protease that plays a pivotal role in invasion and metastasis. © 2002 Wiley-Liss, Inc.


Documento: Artículo
Título:Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells
Autor:Puricelli, L.; Proiettii, C.J.; Labriola, L.; Salatino, M.; Balañá, M.E.; Ghiso, J.A.; Lupu, R.; Pignataro, O.P.; Charreau, E.H.; De Joffé, E.B.K.; Elizalde, P.V.
Filiación:Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina
Instituto de Oncología Angel H. Roffo, Universidad de Buenos Aires, Argentina
Lawrence Berkeley National Laboratories, University of California Berkeley, Berkeley, CA, United States
Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), Obligado 2490, Buenos Aires 1428, Argentina
Palabras clave:ErbB receptors; ERKs; Heregulin; Metastatic mammary tumors; Phosphatidylinositol 3-kinase; 2 (2 amino 3 methoxyphenyl)chromone; epidermal growth factor receptor kinase; gelatinase B; messenger RNA; monoclonal antibody; neu differentiation factor; phosphatidylinositol 3 kinase; recombinant heregulin beta1; STAT protein; unclassified drug; urokinase; wortmannin; animal cell; article; breast tumor; cell migration; cell proliferation; controlled study; enzyme activation; female; metastasis; mouse; nonhuman; priority journal; signal transduction; tumor cell culture; 1-Phosphatidylinositol 3-Kinase; Animals; Blotting, Western; Cell Division; Cell Movement; Dimerization; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Gene Expression Regulation; Humans; Mammary Neoplasms, Animal; Matrix Metalloproteinase 9; Mice; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Neuregulin-1; Phenotype; Phosphorylation; Precipitin Tests; Receptor, Epidermal Growth Factor; Receptor, erbB-2; Receptor, erbB-3; Ribonucleases; Signal Transduction; Time Factors; Tumor Cells, Cultured; Urinary Plasminogen Activator
Página de inicio:642
Página de fin:653
Título revista:International Journal of Cancer
Título revista abreviado:Int. J. Cancer
CAS:1-Phosphatidylinositol 3-Kinase, EC; Enzyme Inhibitors; ERBB4 protein, EC; Flavonoids; heregulin beta1, 155646-83-6; Matrix Metalloproteinase 9, EC; Mitogen-Activated Protein Kinases, EC; Neuregulin-1; PD 98059; Receptor, Epidermal Growth Factor, EC; Receptor, erbB-2, EC; Receptor, erbB-3, EC; Ribonucleases, EC 3.1.-; Urinary Plasminogen Activator, EC


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---------- APA ----------
Puricelli, L., Proiettii, C.J., Labriola, L., Salatino, M., Balañá, M.E., Ghiso, J.A., Lupu, R.,..., Elizalde, P.V. (2002) . Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells. International Journal of Cancer, 100(6), 642-653.
---------- CHICAGO ----------
Puricelli, L., Proiettii, C.J., Labriola, L., Salatino, M., Balañá, M.E., Ghiso, J.A., et al. "Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells" . International Journal of Cancer 100, no. 6 (2002) : 642-653.
---------- MLA ----------
Puricelli, L., Proiettii, C.J., Labriola, L., Salatino, M., Balañá, M.E., Ghiso, J.A., et al. "Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells" . International Journal of Cancer, vol. 100, no. 6, 2002, pp. 642-653.
---------- VANCOUVER ----------
Puricelli, L., Proiettii, C.J., Labriola, L., Salatino, M., Balañá, M.E., Ghiso, J.A., et al. Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells. Int. J. Cancer. 2002;100(6):642-653.