TARGETING OF TRANSFORMING GROWTH FACTOR-ALPHA EXPRESSION TO PITUITARYLACTOTROPHS IN TRANSGENIC MICE RESULTS IN SELECTIVE LACTOTROPH PROLIFERATION AND ADENOMAS

The PRL-secreting cells of the pituitary gland normally express transf orming growth factor-alpha (TGF alpha). To determine the effect of inc reasing TGF alpha expression in the pituitary, a transgenic mouse mode l was created in which overexpression of human TGF alpha was directed to the pituitary lactotrophs using the rat PRL promoter. Of the four g ene-positive mouse lines, two expressed the messenger RNA correspondin g to the transgene in the pituitary glands. However, in both these lin es, expression could only be detected in the female animals. Expressio n of the transgene could be detected as early as 1 month of age, but n o pathology or developmental abnormalities were detected until the ani mals reached 6 months, at which time, hyperplasia of the lactotrophs a ppeared. By the age of 12 months, all of the homozygous transgenic fem ales had developed pituitary adenomas that were immunopositive for PRL . The other hormone-producing cells of the pituitary showed no obvious pathology. The male transgenics developed neither hyperplasia nor ade nomas, nor did the gene-positive transgenic lines that did not express the transgene. In no case was an aggressive pituitary tumor seen. Thi s transgenic mouse model indicates that TGF alpha overexpression by la ctotrophs stimulates the growth of these pituitary cells. Furthermore, TGF alpha has a highly localized action in the pituitary gland, resul ting only in lactotroph hyperplasia and prolactinomas. These observati ons suggest that TGF alpha might play a role in the development of pro lactinomas.