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[Cancer Research 62, 2778-2790, May 15, 2002]
© 2002 American Association for Cancer Research

Carcinogenesis

Transforming Growth Factor ß Signaling Is Disabled Early in Human Endometrial Carcinogenesis Concomitant with Loss of Growth Inhibition1

Trilok V. Parekh, Patricia Gama2, Xie Wen, Rita Demopoulos, John S. Munger, Maria-Luisa Carcangiu3, Michael Reiss and Leslie I. Gold4

Department of Pathology [T. V. P., P. G., R. D., L. I. G.], Kaplan Comprehensive Cancer Center [T. V. P., P. G., R. D., J. S. M., L. I. G.] and Department of Cell Biology and Medicine [J. S. M.], New York University School of Medicine, New York, New York 10016; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut [M-L. C.]; and The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey [X. W., M. R.]

Transforming growth factor ß (TGF-ß), a potent ubiquitous endogenousinhibitor of epithelial cell growth, is secreted as a latent molecule (LTGF-ß)requiring activation for function. TGF-ß signals through the type I(TßRI) and type II (TßRII) receptors, which cooperate to phosphorylate/activate Smad2/3, the transcriptional regulators of genes that induce cell cycle arrest. That carcinomas grow in vivo suggests that they are refractory to TGF-ß. However, this has been difficult to prove because of an inability to analyze the functional status of TGF-ß in vivo as well as lack of close physiological paradigms for carcinoma cells in vitro. The current studies demonstrate that whereas primary cultures of endometrial epithelial cells derived from normal proliferative endometrium (PE; n = 10) were dose-dependently and maximally growth inhibited by 55% ± 5.3% with 10 pM TGF-ß1, endometrial epithelial cells derived from endometrial carcinomas (ECAs; n = 10) were unresponsive (P <= 0.0066). To determine the mechanism of TGF-ß resistance in ECAs, we analyzed the TGF-ß signaling pathway in vivo by immunohistochemistry using specific antibodies to TßRI and TßRII, Smads, and to the phosphorylated form of Smad2 (Smad2P), an indicator of cells responding to bioactive TGF-ß. Smad2P was expressed in all of the normal endometria (n = 25), and was localized to the cytoplasm and nucleus in PE, and only nuclear in the secretory endometrium. In marked contrast, Smad2P immunostaining was weak or undetectable in ECA (n = 22; P <= 0.001) and reduced in glandular hyperplasia (n = 25) compared with normal endometrium. However, total Smad2 and Smad7 (which inhibits Smad2 activation) levels were identical in ECA and normal tissue. Consistent with loss of downstream signaling, both TßRI (n = 19) and TßRII (n = 22) protein expression were significantly reduced in ECA compared with PE (n = 11; P <= 0.05). By in situ hybridization, the mRNA levels of TßRI and TßRII were decreased in the carcinoma cells compared with normal PE glands, suggesting that receptor down-regulation occurs at the transcriptional level. Furthermore, a somatic frameshift mutation in the polyadenine tract at the 5' end of the TßR-II gene was detected in two of six cases examined. Finally, the ability of explants of ECA to activate endogenous LTGF-ß was deficient compared with normal tissue (23.5% versus 7.4%). Therefore, our results suggest that loss of Smad2 signaling in ECA may be because of down-regulation of TßRI and TßRII, and/or decreased activation of LTGF-ß. Because disruption of TGF-ß signaling occurred independent of grade or degree of invasion and was evident in premalignant hyperplasia, we conclude that inactivation of TGF-ß signaling leading to escape from normal growth control occurs at an early stage in endometrial carcinogenesis, thereby defining novel molecular targets for cancer prevention.




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