Heregulin-Induced Growth Factor Receptor Signaling and Breast Carcinogenesis.

We have engineered a panel of BaF3 cell lines that express, singly and in every pairwise combination, the four erbB family receptors. Using this panel of cell lines, we have evaluated hormone-induced erbB family receptor phosphorylation and coupling to downstream signaling proteins and physiologic responses. To date, we have tested six epidermal growth factor EGF family hormones EGF, transforming growth factor alpha TGFcc, heparin-binding EGF-like growth factor HB-EGF, amphiregulin AR, betacellulin BTC, and neuregulin-beta NRGB, also known as heregulin or neu differentiation factor. EGF, BTC, and NRGB exhibit distinct activities, while EGF, TCFQ and HB-ECF are functionally equivalent. Furthermore, the four erbB family receptors exhibit differential coupling to cellular signaling proteins and physiologic responses. This suggests that cellular responses to activation of the EGF familyerbB family signaling network are specified by several hierarchical mechanisms.