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Department of Pathology, Kaplan Comprehensive Cancer Center [L. I. G., B. S., K. R. M., S. G., R. I. D.], and Departments of Environmental Medicine [M. M.] and Gynecology [L. N.], New York University Medical Center, New York, New York 10016, and Department of Medicine and Biological Chemistry, University of California, Irvine, California 92717 [M. K.]
Endometrial carcinoma is associated with antecedent simple and complex hyperplasia, and the endometrium is a target tissue for the action of cytokines and growth factors. Transforming growth factor (TGF)-ßs are potent cellular growth and differentiation regulatory factors. Therefore, we investigated the potential role for TGF-ßs in the normal proliferative endometrium and its possible involvement in the transition to complex hyperplasia and progression to endometrial carcinoma. The angiogenic and mitogenic growth factor, basic fibroblast growth factor, was used for comparison. Differential TGF-ß isoform-specific immunoreactivity was observed in the normal endometrium, which is composed of glandular and stromal cells. There was an increase in TGF-ß3 but not TGF-ß1 or TGF-ß2 in the glandular epithelium from the proliferative to the secretory phase of the menstrual cycle. Immunostaining for TGF-ß2 was more intense in the stroma than the glands. In contrast, TGF-ß1 and TGF-ß3 were near equal intensity in these two endometrial compartments, TGF-ß3 being the most intense. The glandular epithelium demonstrated a statistically significant stepwise increase in the expression of all three TGF-ßs progressing from the normal proliferative endometrium to simple hyperplasia and on to complex hyperplasia. However, the stromal cells maintained approximately the same level of immunoreactivity for TGF-ß in all these samples. In comparing proliferative endometrium with complex hyperplasia, there was a 5.1-, 3.4-, and 2.6-fold increase in immunostaining in the glands for TGF-ß1, TGF-ß2, and TGF-ß3, respectively (P 
0.001). There was no further increase in immunoreactivity with progression from preneoplastic complex hyperplasia to carcinoma. Immunoreactive basic fibroblast growth factor was slight in normal endometrium and simple hyperplasia. There was a 4.6- and 4.2-fold increase in immunostaining observed in complex hyperplasia compared with proliferative endometrium in the glandular (P 0.0054) and stromal (P 0.0053) cells, respectively, with no further increase in carcinoma. By in situ hybridization, an increase in mRNA for all TGF-ß isoforms paralleled TGF-ß immunoreactivity. However, in contrast to the increased immunostaining in the glands in complex hyperplasia, there was remarkably more mRNA in the stromal cell compartment. The discordant expression of mRNA and protein was only observed in the pathological endometrium since both were more highly expressed in the stromal cells in normal proliferative endometrium. This result suggests that there may be a greater paracrine than autocrine mechanism of TGF-ß action in the pathological state. Furthermore, the simultaneous overexpression or accumulation of TGF-ß isoforms and basic fibroblast growth factor, especially in glandular epithelium, with progression from the normal to the hyperplastic state may indicate dysregulated growth control, which may contribute to the development of endometrial carcinoma.
1 Supported by National Cancer Institute Grants CA49507 (to L. I. G.), CA40162 (to M. K.), and CA16087 (to R. I. D.) from the NIH.
2 To whom requests for reprints should be addressed, at New York University Medical Center, 400 East 34th St. RR806, New York, NY 10016.
Received 9/23/93. Accepted 3/ 1/94.
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