Estrogen-induced rat pituitary tumor is associated with loss of retinoblastoma susceptibility gene product

Chronic treatment of rats with the estrogens 17 beta-estradiol or diethylst ilbestrol (DES) induces pituitary tumors in Fischer 344 but not Brown-Norwa y or Sprague-Dawley rats. Functional loss of retinoblastoma susceptibility gene product (pRb), a major regulatory protein for the G1 to S transition o f the cell cycle, has been shown in several tumors. Here we report a decrea sed level of pRb in pituitary rumors of the Fischer 344 rat as compared wit h resistant Sprague-Dawley and Brown-Norway strains. pRb protein levels dec reased 70% in Fischer 344 rats that were treated with diethylstilbestrol fo r 10 weeks as compared with tumor resistant control animals. Interestingly, the F1 hybrid (Fischer 344 x Norway) showed an intermediate range of pRb p rotein expression as compared with those of the parental strains. pRb expre ssion levels in nonhemmorhagic F2 (F1 x F1) rats correlated with the size o f the tumors. One week withdrawal of DES increased pRb levels as compared w ith continuously treated rats. Also, there was a decreased association of c yclin D and cyclin dependent kinase in susceptible tumors, supporting the h ypothesis of a physical and possibly functional loss of pRb in the diethyls tilbestrol-induced pituitary tumor. These results suggest that the differen ce in pRb regulation, whether it is a direct or indirect effect of estrogen , is related to tumor resistance or susceptibility in these two rat strains . (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.