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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

Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792

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 10^-8 M and 10^-7 M. Estradiol at 10^-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 increasing concentrations of EGF (10^-9 M to 10^-7 M). Similarly, the concentration-related rise in PgR caused by estradiol (10^-13 M to 10^-9 M) was abolished after a 7-day pretreatment with EGF (10^-7 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 (P = 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 independence.

¹ Supported by Grants CA32713 and CA14520 and funds awarded through the University of Wisconsin, H. I. Romnes Faculty Fellowship.

² A graduate student in the University of Wisconsin Cellular and Molecular Biology Program.

³ To whom requests for reprints should be addressed, at: Department of Human Oncology, University of Wisconsin Clinical Cancer Center, 600 Highland Avenue, Madison, WI 53792.

Received 5/10/88. Revised 9/30/88. Accepted 11/ 2/88.

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