Regulation of heregulin beta1-induced differentiation in a human breast carcinoma cell line by the extracellular-regulated kinase (ERK) pathway.

The AU565 breast carcinoma cell line was used to determine the role of the extracellular-regulated kinase (ERK) pathway in mediating Heregulinbeta1 (HRGbeta1)-induced mammary cell differentiation. ERK activation remained elevated for 2 h following high doses of HRG which induce differentiation. In contrast, a transient 5 min peak of ERK activation in response to doses of HRG which induce proliferation was observed. A MEK specific inhibitor, PD98059, which inhibited activation of ERK in response to HRG, completely blocked HRG-induced differentiation and reversed cell growth arrest. To further assess the importance of sustained ERK activity in cellular differentiation, we transiently transfected a mutant constitutively active MEK1 construct into AU565 cells. Differentiation was induced in the absence of HRG and treatment with HRG potentiated this response. These data indicate that sustained activation of the MEK/ERK pathway is both essential and sufficient for HRG-induced differentiation of AU565 cells.