Differential actions of the dopamine agonist bromocriptine on growth of SMtTW tumors exhibiting a prolactin and/or a somatotroph cell phenotype: relation to dopamine D2 receptor expression.

Abstract

Dopamine (Da) and Da agonists are known to inhibit secretion and proliferation of normal and tumoral PRL cells, through receptors of D2 subtype. Because of the lack of an experimental model, the relationship between bromocriptine (BR) sensitivity and D2 receptor expression is poorly documented. Such a relationship was analyzed using five lineages of spontaneous transplantable rat pituitary tumors (SMtTW) exhibiting different PRL/GH phenotypes. From plasma PRL and GH concentrations of rats bearing the tumors and tumor messenger RNA contents, tumors were classified as PRL (SMtTW2), somatotroph (SMtTW10), or somatomammotroph (SMtTW5) tumors. Two lineages (SMtTW3 and SMtTW4) represented variants producing PRL and GH but with a high predominance of PRL. With the exception of SMtTW4 tumors, which were malignant, all the tumors were benign and differed in their growth rate. Hormone production and growth of tumors with a PRL or a somatomammotroph phenotype were reduced by about 90% under BR treatment, whereas somatotroph tumors and the PRL malignant tumors were totally insensitive to BR. D2 receptor messenger RNA was present in all BR-sensitive tumors and was not detected in BR-resistant tumors. In conclusion, using five lineages of SMtTW tumors that are representative of the most frequent tumors encountered in human pituitary pathology, we found a full concordance between tumor responses to BR and the expression of D2 receptor by the tumors. The identification of a tumor lineage with a malignant phenotype, secreting high amounts of PRL and presenting a resistance to BR, supports the idea that Da-resistant prolactinomas are aggressive tumors.