Bidirectional interactions between the estrogen receptor and the c‐erbB‐2 signaling pathways: Heregulin inhibits estrogenic effects in breast cancer cells

Thde responsiveness of estrogen receptor (ER)‐positive breast cancer to endocrine therapy is frequently reduced ihd cells over‐expressing c‐erbB‐2. Stimulation of ER suppresses c‐erbB‐2, indicating that estrogen controls the activity of c‐erbB‐2. Heregulin (HRG) has been described to bind to c‐erbB‐3/c‐erbB‐4 and to stimulate c‐erbB‐2. Here we describe the effects of HRG on cell growth and on ER and c‐erbB‐2 expression in breast cancer cell lines containing distinct levels of c‐erbB‐2 and ER (BT‐474: c‐erbB‐2 + + +, ER +; MDA‐MB‐361: c‐erbB‐2 + +, ER ++; MCF‐7: c‐erbB‐2 +, ER + + +). Proliferation of estrogen‐stimulated, c‐erbB‐2 and ER‐positive cells is inhibited by HRG in a dose‐dependent manner. In addition, HRG dose‐dependently inhibits ER expression. Estrogen, however, inhibits c‐erbB‐2. Estrogen‐mediated down‐regulation of c‐erbB‐2 is most pronounced in MCF‐7 but weaker in BT‐474. In the latter cells HRG efficiently blocks the estrogenic effect on c‐erbB‐2. In MCF‐7 cells, however, the inhibition of c‐erbB‐2 cannot be completely reverted by HRG. This modulation occurs in all 3 cell lines at protein, RNA and transcriptional levels, suggesting that the activity of the c‐erbB‐2 promoter, which contains an estrogen‐responsive region, is affected by HRG. The intensity of the mutual inhibition between the HRG/c‐erbB‐2 and the estrogen/ER system depends on the relative levels of ER and c‐erbB‐2 expression in the respective cell lines.