ABSTRACT
Breast cancer mortality has been increasing in Arica Chile where it has surpassed the national rates 11 times between 1990 and 2010. The city of Arica was sprayed with the organophosphrous pesticide malathion in order to control the Mediterranean fly 33 years ago. Moreover we have demonstrated that a malathion treatment induces the formation of breast carcinomas in Sprague Dowley female rats. The objective of this work was to find a relationship between malathion aerial spraying and the increased mortality rate due to breast cancer that has been observed in Arica in recent years. We extracted city data bases with all breast cancer cases diagnosed from 1995 to 2005 from the Dr. Juan Noe Crevani Hospital of Arica city and Ernesto Torres Hospital of Iquique. The number of patients was 100 in Arica and 58 in Iquique, nearby city that has never been sprayed with malathion which had a similar population than Arica in those years. The statistical analysis of the characteristics of the sample related to breast cancer risk showed that there is no significant difference between women from Arica and from Iquique. Nevertheless the patients with more times of exposure to malathion were 5.7-times more likely to be diagnosed with breast cancer (OR= 5.7; p<0.02). In addition, metastases were found in 30.5 percent of the malathion-exposed group and only in 16 percent in the group never exposed (p<0.05). This study suggests that the increase in the mortality rate due to breast cancer occurring in Arica has a significant correlation with the exposure to malathion sprayed over the city more than 30 years ago.
La mortalidad por cáncer de mama ha ido aumentando en Arica Chile, donde ha sobrepasado las tasas nacionales 11 veces entre los años 1990 y 2010. La ciudad de Arica recibió aspersiones del pesticida organofosforado malatión, con el fin de controlar la mosca mediterránea, por primera vez hace 33 años. Por otra parte hemos demostrado que un tratamiento con malatión induce la formación de carcinomas mamarios en ratas hembras Sprague Dowley. El objetivo de este trabajo es encontrar una relación entre las aspersiones con malatión y el aumento en la tasa de mortalidad por cáncer de mama que se ha observado en Arica en los últimos años. Se extrajeron de bases de datos, los casos de cáncer mamario diagnosticados entre 1995 y 2005, en los Hospitales Dr. Juan Noé Crevani de Arica y Ernesto Torres de Iquique. El número de pacientes diagnosticados con cáncer de mama fue 100 en Arica y 58 en Iquique, ciudad que nunca fue fumigada con malatión y con una población similar a la de Arica durante esos años. El análisis estadístico de las características de la muestra, en relación a los factores de riesgo de cáncer mamario, mostró que no hay diferencia significativa entre las mujeres de Arica y de Iquique. Sin embargo, las mujeres con mayor tiempo de exposición al malatión fueron 5,7 veces más propensas a ser diagnosticadas con cáncer de mama (OR = 5,7, p <0.02). Además el 30,5 por ciento del grupo expuesto a malatión presentó metástasis y en el grupo no expuesto sólo el 16 por ciento (p <0.05). Este estudio sugiere que el aumento de la tasa de mortalidad por cáncer de mama que se ha producido en Arica tiene una correlación significativa con la exposición al malatión esparcido sobre la ciudad hace más de 30 años.
Subject(s)
Humans , Female , Cholinesterase Inhibitors/adverse effects , Malathion/adverse effects , Breast Neoplasms/mortality , Pesticides/adverse effects , Chile/epidemiology , Organophosphorus Compounds/adverse effects , Public HealthABSTRACT
The specific signaling connections between the mitogen-activated protein kinases (MAPK) such as c-Jun N-terminal kinase (JNK-1) and phosphatases PP4 and M3/6, affecting the family of early nuclear factors, is complex and remains poorly understood. JNK-1 regulates cellular differentiation, apoptosis and stress responsiveness by up-regulating early nuclear factors such as c-Jun, a member of the activating protein (AP-1) family, and the Early Growth Factor (EGR-1). C-Jun, when phosphorylated by c-Jun N-terminal kinase (JNK-1) associates with c-Fos to form the AP-1 transcription factor that activates gene expression. We have investigated the regulation of the JNK-1 kinase by co-transfecting phosphatases PP4 and M3/6 in prostate cancer cell lines PC-3 and LNCaP, which have been previously stimulated with human EGF or cisplatin. Co-transfections of plasmids expressing the JNK-1 and the serine/threonine phosphatases PP4 resulted in a significant increase in JNK-1 activity in both PC3 and LNCaP cells. In contrast, co-transfection of JNK-1 with the dual specific phosphatase serine/threonine M3/6 showed only a marginal effect in JNK-1 activity. The phosphatase M3/6 also failed in blocking the induction of JNK-1 activity observed in presence of PP4. The higher activity of JNK-1 was associated with increased activities of the factors c-Jun/AP-1 and EGR-1. This suggests that JNK-1 activity in PC-3 and LNCaP cells requires not only active PP4 for stable maintenance but also suggests that the relative degree of phosphorylation of multiple cellular components is the determinant of JNK-1 stability.
Subject(s)
Humans , Phosphoprotein Phosphatases/analysis , Phosphoprotein Phosphatases/biosynthesis , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/chemical synthesis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/immunology , Prostatic Neoplasms/chemistry , Protein Kinases/biosynthesis , Protein Kinases/genetics , Protein Kinases/chemistry , Apoptosis/physiology , Apoptosis/genetics , PhosphorylationABSTRACT
To mimic the two-signal requirements for T cell activation mediated by ligands, we exposed the superantigens SEA or SEE (signal 1) to T cells incubated with HLA-DR/LFA-3 or HLA-DR/B7-1-CHO transfected cells (signal 2). LFA-3 costimulation was able to induce T cell proliferation as well as IFN-g and IL-4 production at similar levels as in cells induced by B7-1. Analysis of the CD28RE of the IL-2 promoter showed specific transcription factor recruitment at the CD28RE element upon induction by B7-1/SEE. Further functional studies with an IL-2 enhancer-promoter carrying either wild type or mutated versions of the CD28RE site revealed that this element is necessary for full activation upon B7-1 costimulation. While both CD28/B7-1 and CD2/LFA-3 costimulation resulted in the up-regulation of IL-4 and IFN-g promoters, IL-2 promoter activity and production of IL-2 were only seen after B7-1 costimulation. However, contrary to what has been previously proposed, we show that costimulation with either B7-1 or LFA-3 further enhanced the ERK-2 activity and strongly activated the p38 MAPK pathway, but only B7-1 costimulation induced high levels of JNK-1 activity. These data suggest that the differential effect of CD28 vs. CD2 can be related to the difference in the ability of the two pathways to induce JNK-1 activity