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Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 Growth Factor Receptors and Their Ligands, Neuregulin-1 , Neuregulin-1 , and Betacellulin, in Normal Endometrium and Endometrial Cancer

Receptor Biology Laboratory, Imperial Cancer Research Fund Molecular Oncology Unit [R. S., E. B., W. J. G.], Division of Investigative Sciences [F. M.], Imperial College School of Medicine, Hammersmith Campus, London W12 0NN, and Oncology Department, The Royal Surrey County Hospital, Guildford, Surrey GU2 5XX [H. T.], United Kingdom

The objective of this study was to determine the immunohistochemical expression of the c-erbB-3 and c-erbB-4 growth factor receptors and their principal ligands, the neuregulins and betacellulin, in normal endometrium and determine whether there was evidence of under- or overexpression in endometrial adenocarcinoma. Immunohistochemistry was performed using well-characterized antibodies against each of the five proteins analyzed on formalin-fixed, paraffin-embedded archival material. Forty-three normal endometrial samples (16 proliferative, 19 secretory, and 8 hyperplastic) and 41 endometrial adenocarcinoma cases were analyzed. There was variable expression of the growth factor receptors and the ligands in the two principal phases of the menstrual cycle as well as in endometrial adenocarcinoma. In normal endometrium, the c-erbB-3 receptor was weakly expressed in both phases. The c-erbB-4 receptor and all of the ligands examined, neuregulin , neuregulin , and betacellulin, were expressed at significantly higher levels in the secretory as compared with the proliferative phase of the menstrual cycle, suggesting a role for these proteins in endometrial maturation. In endometrial adenocarcinoma, overexpression of c-erbB-3, c-erbB-4, and betacellulin with underexpression of neuregulin as compared with normal controls was observed. Neuregulin expression was not found to be significantly different in the two groups. These results suggest that signaling through the c-erbB-3 and c-erbB-4 receptors and the ligands neuregulin , neuregulin , and betacellulin are important in endometrial carcinogenesis.

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