Decrease in Estradiol-stimulated Progesterone Receptor Production in MCF-7 Cells by Epidermal Growth Factor and Possible Clinical Implication for Paracrine-regulated Breast Cancer Growth1

These studies have evaluated the modulation by epidermal growth factor (EGF) of estrogen receptor (ER) levels and estradiol-stimulated progesterone receptor (PgR) synthesis. Short-term culture of MCF-7 cells in an "estrogen (phenol red indicator)-free" environment caused a rise in ER concentration that is inhibited by EGF at IO"8M and 10~7M. Estradici at 10~'° M induced a 5-fold increase of PgR over a 5-day assay period. However, the rise in PgR was diminished or prevented by increas ing concentrations of EGF (10~' M to 10~7M). Similarly, the concentra tion-related rise in PgR caused by estradiol (10~13M to 10~' M) was abolished after a 7-day pretreatment with EGF (1(T7 M). For both the ER and PgR receptor, EGF treatment caused a decrease in receptor number without an apparent change in receptor affinity. Thus, EGF appears to down regulate the ER by approximately 50% and to diminish the ability of estradiol to induce PgR. In addition, a survey of ER*PgR+ and ER*PgR" values of primary breast tumors from women between the ages of 55 and 70 demonstrated significantly less (50%) (85 to 39 fmol/ mg of cytosol protein) ER in ER*PgR~ tumors (/' = 0.0005). The median PgR values for the PgR-positive tumors were 139 fmol/mg of cytosol protein. We propose that ER* breast cancer that has changed to a paracrine growth factor-driven system (from stromal cells or ER~ breast cancer cells) is less responsive to gonadal steroids. The loss of PgR in these ER+ carcinomas may be an indicator of this type of hormone