ANTISENSE ESTROGEN-RECEPTOR RNA EXPRESSION INCREASES EPIDERMAL GROWTH-FACTOR RECEPTOR GENE-EXPRESSION IN BREAST-CANCER CELLS

In human breast cancer, progression to a more malignant phenotype is o ften accompanied by decreased expression of estrogen receptor (ER) and increased expression of epidermal growth factor receptor (EGFR). High er levels of this receptor tyrosine kinase are found in tumors lacking ER, and a quantitative, inverse relationship exists between the level of ER and EGFR mRNA in human breast cell lines, Antisense ER (ASER) R NA was used to evaluate the consequence of decreased ER expression in breast cancer cells, specifically to determine whether ER is involved in the regulation of EGFR gene expression, ER-positive MCF-7 human bre ast cancer cells were transfected with ASER, and clones constitutively expressing ASER RNA had decreased ER and up to a 3-fold increase in t he expression of EGFR mRNA, To confirm that this observation was a dir ect consequence of ASER expression, a metal-inducible ASER expression construct was transfected into MCF-7 cells, and transfected clones wer e isolated and characterized. Northern analysis revealed an induction of ASER RNA within 1 h of the addition of zinc, which was followed by a 4-fold increase in EGFR mRNA levels, maximal at 6-12 h. The basal le vel of expression of the glucocorticoid receptor is also inversely rel ated to that of ER among breast cancer cell lines, but neither constit utive nor inducible expression of ASER affected the expression of gluc ocorticoid receptor, These data support the hypothesis that the level of expression of ER specifically influences the expression of EGFR in human breast cancer cells and provides a potential link between loss o f steroid sensitivity and the acquisition of autonomous growth.