Differential signal transduction of epidermal‐growth‐factor receptors in hormone‐dependent and hormone‐independent human breast cancer cells

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Abstract
In breast cancer, hormone dependency is inversely correlated with the number of surface epidermal‐growth‐factor (EGF) receptors on the tumor cells. In vitro, EGF stimulated only hormone‐dependent immortalized human breast cancer cells to grow with an increased rate whereas hormone‐independent cells were not affected by EGF. The number of EGF surface receptors is about 5–10‐times smaller on hormone‐dependent cells than on hormone‐independent cells. Two cell lines representing the two cell types were used to demonstrate the signal‐transduction capabilities of the EGF receptors. The two cell lines were the hormone‐dependent MCF‐7 cells and the hormone‐independent MDA‐MB‐231 cells. Incubation at 37°C for 15 min with 10−8 M EGF increased the surface EGF‐receptor density substantially on MCF‐7 cells (50%) and reduced the number of these receptors on MDA‐MB‐231 cells to about 65% of the control. Both cell lines internalized a fluoresceinisothiocyanate‐labeled EGF with similar kinetics. EGF triggered tyrosine phosphorylation of several targets in isolated MCF‐7 cell membranes. One of these targets was shown by immuno‐precipitation to be the EGF receptor. In MDA‐MB‐231 cell membranes, the EGF receptor was demonstrated to be the main target for tyrosine phosphorylation. The mRNA expression of the immediate early proto‐oncogene c‐fos was stimulated by EGF only in MCF‐7 cells. In contrast, the mRNA of the EGF receptors was stimulated by EGF in both cell lines. These results demonstrate that, although EGF‐binding sites are present on both cell lines, their signal‐transduction capacity and activities are substantially different and resulted in a divergent response of the two cell types to EGF.