ACTIVATION AND FUNCTION OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR AND ERBB-2 DURING MAMMARY-GLAND MORPHOGENESIS

The hormonal stimulation of mammary gland morphogenesis is believed to occur through growth factor receptor signaling pathways, To determine the importance of the epidermal growth factor receptor (EGFR) pathway , we examined extracts of inguinal mammary glands from prepubertal and pubertal mice for tyrosine-phosphorylated EGFR and other erbB recepto rs, Tyrosine phosphorylation of both EGFR and erbB-2 was detected in n ormal female BALB/c mice at 5-6 weeks of age, but not during the prepu bertal stage, e.g., 24 days of age, Treatment of mice with estradiol o r epidermal growth factor also stimulated the formation of mammary EGF R/erbB-2 phosphotyrosine, Waved-P mice, which have impaired EGFR kinas e activity, exhibited less mammary development than did wild-type (wt) mice when both were evaluated at 36 days of age, Because EGFR knockou t (KO) mice die shortly after birth, glands from the newborns were imp lanted under the renal capsules of female nude mice. Under these condi tions, extensive ductal growth was observed in mammary glands from wt animals; in contrast, glands from EGFR KO mice failed to grow beyond r udimentary structures. Tissue recombinants revealed that the wt fat pa d supported the morphogenesis of EGFR KO epithelium, whereas the EGFR KO fat pad did not. Taken together, these data suggest that EGFR is es sential for morphogenesis of the mammary ducts and functions during th is period of mammary development as a heterodimer with erbB-2 in the m ammary stroma.