Mitogenic signaling induced by tumor necrosis alpha (TNF-A) in mouse mammary tumor cells

RIVAS MA; ROSEMBLIT C; CARNEVALE R; SALATINO M; PROIETTI CJ; CHARREAU EH; ELIZALDE PV; SCHILLACI R

Buenos Aires

Jornada; V Jornadas Multidisciplinarias de la Sociedad Argentina de Biología (SAB); 2004

Sociedad Argentina de Biología (SAB)

The presence of interactions between TNF-a and progestins remains poorly characterized. In this study, we investigated TNF-a effects on the proliferation of an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female Balb/c mice. TNF-a stimulated a dose-dependent proliferation of primary cultures of C4HD epithelial cells, from the MPA-induced mammary tumor model. In addition, TNF-a treatment of C4HD cells induced a strong degree of activation of p42/p44 mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI-3K)/Akt signaling pathways. Inhibition of p42/p44 MAPK with the selective MEK1 inhibitor PD98059 and of PI-3K/Akt with wortmannin or LY294002, resulted in significant reduction of TNF-a capacity to stimulate growth of C4HD cells. These findings demonstrate the involvement of both pathways in TNF-a -induced proliferation of C4HD breast tumor cells. Simultaneous addition of MPA and TNF-a to primary cultures of C4HD cells significantly enhanced MPA growth stimulatory effects. Moreover, TNF-a treatment of C4HD cells for 48 h induced 2-3-fold increase in progesterone receptor (PR) number, as measured by a binding assay with 3H R5020. These results provide the first demonstration that TNF-a enhances progestin-mediated proliferation of breast cancer cells through the up-regulation of PR expression.