Inhibition of Estrogen Receptor Coactivator Expression by Antisense Oligodeoxynucleotides and Effect on Breast Cancer Cell Proliferation and Gene Expression

摘要

Coactivators are nuclear proteins that interact with steroid receptors, such as estrogen receptor-alpha (ERalpha), and are required for the ability of receptors to stimulate the expression of target genes. Antiestrogen ligand are commonly utilized in the treatment of breast cancer to negatively regulate the activity of steroid receptors. However, tumors often can develop resistance to antiestrogen therapy. Therefore, as an alternative approach to inhibiting ERalpha function in breast cancer cells, we have developed antisense oligonucleotides against three of the major ERalpha coactivator proteins. These oligonucleotides decrease the expression of coactivator mRNA and protein, and in so doing, decrease the ability of ERalpha to stimulate gene expression. These oligonucleotides also decrease the proliferation of MCF-7 breast cancer cells in response to estrogen treatment. Taken together, anti sense oligonucleotide technology has the potential to regulate ERalpha action at a level that circumvents ligand control, and therefore represents a novel mechanism by which to inhibit breast cancer gene expression and proliferation, and potentially to regulate the growth of breast cancer.