REGULATION OF RETINOBLASTOMA GENE-EXPRESSION IN HORMONE-DEPENDENT BREAST-CANCER

Studies have shown an increased risk for breast cancer in the mothers of children suffering from retinoblastoma and osteosarcoma, suggesting a role for the retinoblastoma susceptibility (Rb) gene product in bre ast cancer. We now show that estradiol decreases the expression of Rb at the level of protein and messenger RNA (mRNA) in estrogen-dependent breast cancer cell lines. Treatment of MCF-7 cells with 10(-9) M estr adiol for 48 h resulted in a 70% decrease in the level of Rb protein. Ribonuclease protection assays showed a 50% decrease in the steady sta te levels of Rb mRNA by 12 h and a 70% decrease in Rb mRNA by 24 h. Tr eatment with estradiol had no effect on the rate of Rb gene transcript ion or on Rb mRNA stability, but resulted in an increase in the steady state level of Rb mRNA in the nucleus. The effect of estradiol was in hibited by 10(-7) M 4-hydroxytamoxifen. In the absence of estradiol, t he antiestrogens 4-hydroxytamoxifen and ICI 164,384 increased Rb mRNA by 50% over that in estrogen-depleted conditions. Estradiol regulation of Rb mRNA also occurred in other estrogen-dependent breast cancer ce ll lines. Insulin-like growth factor I, insulin, progestins, and epide rmal growth factor had no effect on Rb expression. In summary, these r esults show that estradiol specifically regulates the expression of th e Rb susceptibility gene product in hormone-dependent breast cancer by a posttranscriptional mechanism that occurs in the nucleus. The resul ts from this study suggest that the negative regulation of Rb expressi on by estradiol, rather than Rb loss or mutation, may play an importan t role in breast carcinogenesis.