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

✍ Scribed by Thomas W. Grunt; Miguel Saceda; Mary Beth Martin; Ruth Lupu; Evelyn Dittrich; Georg Krupitza; Hanna Harant; Heinz Huber; Christian Dittrich

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: French
• Weight: 993 KB
• Volume: 63
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910630417

✦ Synopsis

The responsiveness of estrogen receptor (ER)-positive breast cancer to endocrine therapy is frequently reduced in 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-36 I: 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, how- ever, 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 HRC 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/ERsystem depends on the relative levels of ER and c-erbB-2 expression in the respective cell lines.