OPPOSITE EFFECT OF A CAMP ANALOG ON TUMORAL GROWTH-RELATED TO HORMONEDEPENDENCE OF A MURINE MAMMARY-TUMOR

Interactions among transcription factors are one of the mechanisms tha t regulate gene expression. Through protein-protein associations diffe rent signaling pathways become connected and the message triggered by each of the molecules involved can modify other related routes. In a m urine mammary tumor induced by medroxyprogesterone acetate (MPA), furt her treatment with this agent showed a different response on tumor gro wth. In one group of tumors, growth rate was increased (hormone depend ent, HD), whereas in the other group the progestin agent failed to mod ify the rate of tumor development (hormone autonomous, HA). Progestero ne receptors (PgR) and estrogen receptors (ER) were expressed in both groups. Administration of 8-CI-cAMP, a cAMP analogue, stimulated tumor growth in the HD subline and inhibited growth in the HA subline. Simu ltaneous administration of 8-CI-cAMP and MPA resulted in suppression o f inhibitory 8-CI-cAMP action in the HA tumor subline attributable to changes in molecular configuration of protagonic members of each signa ling pathway, whereas in the HD subline growth was additive as if each of the pathways were acting separately. MPA induced down regulation o f PgR in both tumor sublines and up regulation of ER in the C4-HD subl ine. The effect of 8-CI-cAMP alone or associated with MPA was more com plex and variations in PgR and ER content by themselves are insufficie nt to explain changes in tumoral growth. A model consistent with our e xperimental findings is presented.