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Loss of c-myc Repression Coincides with Ovarian Cancer Resistance to Transforming Growth Factor ß Growth Arrest Independent of Transforming Growth Factor ß/Smad Signaling¹

Division of Gynecologic Oncology, Cedars-Sinai Medical Center, Los Angeles, California 90048 [R. L. B., H. T., B. Y. K.], and Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90024 [R. L. B., B. Y. K.]

Many epithelial carcinomas, including ovarian, are refractory to the antiproliferative effects of transforming growth factor (TGF) ß. In some cancers, TGF-ß resistance has been linked to TGF-ß receptor II (TßR-II) and Smad4 mutations; however, in ovarian cancer, the mechanism of resistance remains unclear. Primary ovarian epithelial cell cultures were used as a model system to determine the mechanisms of TGF-ß resistance. To simulate in vivo responses to TGF-ß, primary cultures derived from normal human ovarian surface epithelium (HOSE) and from ovarian carcinomas (CSOC) were grown on collagen I gel, the predominant matrix molecule in the ovarian tumor milieu. When treated with 5 ng/ml TGF-ß for 72 h, HOSE (n = 11) proliferation was inhibited by 20 ± 21% on average. In contrast, CSOC (n = 10) proliferation was stimulated 5 ± 10% in response to TGF-ß (a statistically significant difference in response when compared with HOSE; P = 0.001). To dissect the TGF-ß/Smad signaling pathway we used a quantitative RNase protection assay (RPA) for measuring mRNA levels of TGF-ß pathway components in 20 HOSE and 20 CSOC cultures. Basal mRNA levels of TGF-ß receptors I and II, downstream signaling components Smad2, 3, 4, 6, 7, and the transcriptional corepressors Ski and SnoN did not show a statistically significant difference between HOSE and CSOC, and cannot explain their differential susceptibility to TGF-ß-induced cell cycle arrest. To assess functional differences of the TGF-ß pathway in TGF-ß-sensitive HOSE and TGF-ß-resistant CSOC, we measured Smad2/4 and 3/4 complex induction after TGF-ß treatment. HOSE and CSOC showed equivalent Smad2/4 and 3/4 complex induction after TGF-ß exposure for 0, 0.5, 2, and 4 h. It has been proposed that SnoN and Ski are corepressors of the TGF-ß/Smad pathway and undergo TGF-ß-induced degradation followed by reinduction of SnoN mRNA. However, our data show equivalent SnoN degradation in HOSE and CSOC, and equivalent SnoN mRNA induction after TGF-ß treatment. Surprising, TGF-ß-induced Ski degradation was not observed in HOSE or CSOC, suggesting that Ski may not function as a TGF-ß/Smad corepressor in ovarian epithelial cells. These data implied that the TGF-ß/Smad pathway remains functional in CSOC, although CSOC cells are resistant to antimitogenic TGF-ß effects. CSOC resistance to TGF-ß coincided with the loss of c-myc down-regulation. These data suggest that TGF-ß/Smad signaling is blocked downstream of Smad complex formation or that an alternate signaling pathway other than TGF-ß/Smad may transmit TGF-ß-induced cell cycle arrest in the ovarian epithelium.

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