The increased levels of c‐Myc protein observed previously in an ovarian carcinoma cell line stably transfected to express HER2 has suggested a role for the HER2 pathway in c‐Myc expression. Analysis of HER2‐transfected cells stimulated with heregulin β1 (HRG) revealed increased c‐Myc protein levels but not a corresponding increase in c‐Myc mRNA expression or any change in c‐Myc protein half‐life. Transfection of HER2‐overexpressing cells with a construct containing the 5′ untranslated region (5′UTR) of c‐Myc mRNA originated from the P2 promoter and placed upstream of the Renilla luciferase gene, enhanced reporter expression upon stimulation with HRG. The HRG‐mediated increase in reporter activity correlated with the HRG‐mediated induction observed for c‐Myc protein, identifying the P2‐derived leader (P2L) of c‐Myc mRNA as the cis‐element involved in c‐Myc translational induction. Both the increase in c‐Myc protein levels and P2L‐enhanced translational activity were inhibited by the PI3K inhibitor wortmannin. Together, these results demonstrate that HRG stimulation of HER2 overexpressing cells leads to enhanced c‐Myc protein synthesis through activation of the PI3K/Akt/mTOR pathway and that the P2L of c‐Myc mRNA is the element responsible for induction of c‐Myc translation. © 2004 Wiley‐Liss, Inc.