BIDIRECTIONAL INTERACTIONS BETWEEN THE ESTROGEN-RECEPTOR AND THE C-ERBB-2 SIGNALING PATHWAYS - HEREGULIN INHIBITS ESTROGENIC EFFECTS IN BREAST-CANCER CELLS

The responsiveness of estrogen receptor (ER)-positive breast cancer to endocrine therapy is frequently reduced in cells over-expressing c-erB-2. Stimulation of ER suppresses c-erbB-2, indicating that estrogen controls the activity of c-erB-2. Heregulin (HRG) has been described to bind to c-erB-3/c-erbB-4 and to stimulate c-erB-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. (C) 1995 Wiley-Liss, Inc.