Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta, and betacellulin, in normal endometrium and endometrial cancer

The objective of this study was to determine the immunohistochemical expres sion of the c-erbB-3 and c-erbB-4 growth factor receptors and their princip al ligands, the neuregulins and betacellulin, in normal endometrium and det ermine whether there was evidence of under- or overexpression in endometria l adenocarcinoma, Immunohistochemistry was performed using well-characteriz ed antibodies against each of the five proteins analyzed on formalin-fixed, paraffin-embedded archival material. Forty-three normal endometrial sample s (16 proliferative, 19 secretory, and 8 hyperplastic) and 41 endometrial a denocarcinoma cases were analyzed. There was variable expression of the gro wth factor receptors and the ligands in the two principal phases of the men strual cycle as well as in endometrial adenocarcinoma. In normal endometriu m, the c-erbB-3 receptor was weakly expressed in both phases. The c-erbB-4 receptor and all of the ligands examined, neuregulin alpha, neuregulin beta , and betacellulin, were expressed at significantly higher levels in the se cretory as compared with the proliferative phase of the menstrual cycle, su ggesting a role for these proteins in endometrial maturation. In endometria l adenocarcinoma, overexpression of c-erbB-3, c-erbB-4, and betacellulin wi th underexpression of neuregulin alpha as compared with normal controls was observed. Neuregulin beta expression was not found to be significantly dif ferent in the two groups. These results suggest that signaling through the c-erbB-3 and c-erbB-4 receptors and the ligands neuregulin alpha, neureguli n beta, and betacellulin are important in endometrial carcinogenesis.