Morphogenetic and proliferative responses to heregulin of mammary epithelial cells in vitro are dependent on HER2 and HER3 and differ from the responses to HER2 homodimerisation or hepatocyte growth factor

The effects of heregulin on the cell line HB2, derived from immortalised hu man luminal mammary epithelial cells, have been examined. HB2 cells, which normally form smooth spherical colonies in collagen gels, exhibited a strik ing heregulin-induced morphological change to colonies projecting a large n umber of spiky branches. A mitogenic effect of heregulin on HB2 cells was a lso seen, which was more pronounced on collagen than on plastic, whereas ce ll motility was unaffected. HB2 cells were found to express the heregulin r eceptor subunits HER2 and HER3, but not HER4. Treatment of HB2 cells with h eregulin also induced tyrosine phosphorylation of a band shown by immunopre cipitation to contain HER3. Using specific receptor-blocking antibodies, it was found that both the morphogenetic and proliferative responses of hereg ulin in HB2 cells were mediated by HER2 and HER3. To compare the effects of HER3 in heregulin signaling to heregulin-independent HER2 homodimerisation (thought to be a carcinoma-associated event), HB2 cells were transfected w ith the trk-neu hybrid receptor which could be induced to form homodimers b y NGF. Although activated HER:! homodimers induced proliferation in the HB2 transfectants in collagen, a morphological response in collagen was not se en, suggesting that HER3 signaling is important for morphogenesis in this c ell type.