Activation of the epidermal growth factor receptor (EGFR) family is thought to play an important role in mammary tumorigenesis and metastasis. The potent transforming activity of the EGFR family is due to their ability to heterodimerize with each other in response to a number of mitogenic ligands. The formation of EGFR and ErbB-2 heterodimers has been recently implicated as an important factor in the induction of sporadic human breast cancers. To directly assess whether the catalytic activity of EGFR is required for ErbB-2 induction of mammary tumors, we have interbred transgenic mice expressing ErbB-2 oncogene under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter/enhancer to a naturally occurring mouse mutant carrying a catalytically impaired EGFR (waved-2 mice). Although the female transgenic mice possessing mutant EGFR developed mammary tumors, the tumors occurred only after a delayed latency period, and were fewer in number. The impaired tumor phenotype was further correlated with debilitated phosphorylation of the Gab1 multisubstrate adapter. These observations provide evidence that efficient ErbB-2-induced mammary tumor progression requires EGFR-dependent activation of Gab1.