Differential Effects of Histamine-mediated Signaling Processes in Normal and Malignant Human Mammary Cells.

MEDINA VANINA; CRICCO GRACIELA; GARBARINO GLORIA; NUÑEZ MARIEL; MARTIN GABRIELA; COCCA CLAUDIA; BERGOC ROSA; RIVERA ELENA

Mayo 11-14, 2005, Bled, Eslovenia.

Congreso; European Histamine Research XXXIV Annual Meeting,; 2005

Differential Effects of Histamine-mediated Signaling Processes in Normal and Malignant Human Mammary Cells.   Vanina Medina, Graciela Cricco, Gloria Garbarino, Mariel Núñez, Gabriela Martín, Claudia Cocca, Rosa M. Bergoc, Elena S. Rivera Radioisotopes Laboratory, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956 , 1113 Buenos Aires, ARGENTINA. The role of histamine (HA) in the growth of normal and cancer cells has been extensively investigated. We have previously reported that in rat normal mammary gland HA behaves as a mediator of cell growth under the control of specific growth factors. In experimental mammary carcinomas HA becomes an autocrine growth factor capable of regulating cell proliferation via H1R and H2R, as one of the first steps responsible for the onset of malignant transformation. The aim of the present work was to investigate the differential signal transduction pathways in response to HA in normal (HBL-100) and cancer (MDA-MB-231) cells derived from human mammary gland. For that purpose we performed: proliferation and differentiation assays and cell cycle analysis. We also evaluated the reactive oxygen species levels and the expression of proteins related to proliferation, differentiation and apoptosis by flow cytometry. HA content was assessed by immunostaining and fluorescence was determined by flow cytometry and confocal microscopy. In MDA-MB-231 cells, HA treatment modulated proliferation in a dose-dependent manner. HA 10 mM via H2R increased camp production and H2O2 levels, decreased endogenous HA content as well as BCL-2, ERK1/2 and P38 proteins, produced cell cycle arrest in G2/M and induced the expression of differentiation markers with the subsequent suppression of cell proliferation. In addition, HA at doses below 100 nM activated PLC via H1R, enhancing cell proliferation and reducing H2O2 levels. In contrast, in HBL-100 cells, HA content was significantly lower while exogenous HA only decreased cell growth at doses below 100 nM. Both H1R and H2R were coupled to PLC activation and increased H2O2 levels. This study indicates that HA regulates differentially proliferation of normal and cancer cells representing a promising target for the development of specific breast cancer therapies.