Ribozyme-mediated cleavage of the estrogen receptor messenger RNA and inhibition of receptor function in target cells

Estrogen receptor (ER) functions as a ligand-activated transcription factor for estrogen-regulated genes. Because of the critical role of the ER in th e proliferation of certain estrogen-dependent cancer cell types such as the mammary tumor, inhibitors of estrogen action at the level of receptor func tion are of major clinical interest. Here we describe developments of two r ibozymes that can selectively degrade the human ER mRNA and inhibit trans-a ctivation of an artificial promoter containing the estrogen response elemen t. Two ribozymes, designated RZ-1 and RZ-2, cleave the human ER alpha mRNA at nucleotide positions +956 and +889, respectively. These cleavage sites l ie within the coding sequence for the DNA-binding domain of the receptor pr otein. Both RZ-1 and RZ-2 were also effective in inhibiting the progression of quiescent MCF-7 breast cancer cells to the S phase of the cell cycle af ter their exposure to 17 beta-estradiol (10(-9) M). These results provide a new avenue for inhibition of estrogen action by selective mRNA degradation with its potential therapeutic application through targeted gene delivery vectors.