Opposite effect of a cAMP analogue on tumoral growth related to hormone dependence of a murine mammary tumor.

Abstract

Interactions among transcription factors are one of the mechanisms that regulate gene expression. Through protein-protein associations different signaling pathways become connected and the message triggered by each of the molecules involved can modify other related routes. In a murine mammary tumor induced by medroxyprogesterone acetate (MPA), further treatment with this agent showed a different response on tumor growth. In one group of tumors, growth rate was increased (hormone dependent, HD), whereas in the other group the progestin agent failed to modify the rate of tumor development (hormone autonomous, HA). Progesterone 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. Simultaneous administration of 8-CI-cAMP and MPA resulted in suppression of inhibitory 8-CI-cAMP action in the HA tumor subline attributable to changes in molecular configuration of protagonic members of each signaling pathway, whereas in the HD subline growth was additive as if each of the pathways were acting separately. MPA induced down regulation of PgR in both tumor sublines and up regulation of ER in the C4-HD subline. The effect of 8-CI-cAMP alone or associated with MPA was more complex and variations in PgR and ER content by themselves are insufficient to explain changes in tumoral growth. A model consistent with our experimental findings is presented.