REDUCTION IN THE EXPRESSION AND ACTION OF TRANSFORMING GROWTH-FACTOR-BETA-1 ON LACTOTROPES DURING ESTROGEN-INDUCED TUMORIGENESIS IN THE ANTERIOR-PITUITARY

We have previously shown that transforming growth factor beta 1 (TGF-b eta 1) receptor and TGF-beta type II receptor (T beta R-II) are produc ed in lactotropes, and that TGF-beta 1 inhibits the growth of these an terior pituitary cells by an autocrine mechanism. To study the changes of the expression and function of this growth factor during tumorigen esis, we have measured the levels of TGF-beta 1 and T beta R-II mRNAs and proteins in the normal and tumor anterior pituitary cells in vivo and in vitro and have compared the cell growth responses to TGF-beta 1 in normal and tumor pituitary cells in vitro. Treatment with estradio l-17 beta for 1, 2, 4, and 8 weeks caused a time-dependent increase in pituitary protein, prolactin, and prolactin mRNA levels and in plasma prolactin levels, suggesting that estrogen enhanced lactotropic proli feration in anterior pituitary glands. The levels of TGF-beta 1 protei n and mRNA in anterior pituitary tissues were reduced over time after estrogen treatment during the development of pituitary tumors. The mRN A and protein levels of T beta R-II decreased markedly during the deve lopment of pituitary tumors. In addition, two transformed lactotropes, GH3 and PR1 cell lines, showed markedly reduced levels of TGP-beta 1 as well as T beta R-II mRNA. Comparison of the antiproliferative effec ts of TGF-beta in transformed and normal lactotropes in cultures revea led that the sensitivity of GH3 cells is reduced, and that PR1 cells a re virtually resistant to TGF-beta 1. These data suggest that substant ial changes in TGF-beta 1 expression and function occur during estroge n-induced tumorigenesis in the anterior pituitary.