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

Abstract

Chronic treatment of rats with the estrogens 17 β-estradiol or diethylstilbestrol (DES) induces pituitary tumors in Fischer 344 but not Brown–Norway or Sprague–Dawley rats. Functional loss of retinoblastoma susceptibility gene product (pRb), a major regulatory protein for the G1 to S transition of the cell cycle, has been shown in several tumors. Here we report a decreased level of pRb in pituitary tumors of the Fischer 344 rat as compared with resistant Sprague–Dawley and Brown–Norway strains. pRb protein levels decreased 70% in Fischer 344 rats that were treated with diethylstilbestrol for 10 weeks as compared with tumor resistant control animals. Interestingly, the F1 hybrid (Fischer 344×Norway) showed an intermediate range of pRb protein expression as compared with those of the parental strains. pRb expression levels in nonhemmorhagic F2 (F1×F1) rats correlated with the size of the tumors. One week withdrawal of DES increased pRb levels as compared with continuously treated rats. Also, there was a decreased association of cyclin D and cyclin dependent kinase in susceptible tumors, supporting the hypothesis of a physical and possibly functional loss of pRb in the diethylstilbestrol-induced pituitary tumor. These results suggest that the difference 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.