Anomalies of the TGF-β postreceptor signaling pathway in ovarian cancer cell lines

Transforming growth factor-β (TGF-β) can cause cell cycle arrest, terminal differentiation, or apoptosis in most normal epithelial cells, whereas most malignant cell lines are resistant to TGF-β. Mechanisms of resistance to TGF-β caused by modulation of cell cycle regulators and/or inactivation of components of the TCF-β signaling transduction pathway such as C-myc and Smad4 have been demonstrated in human pancreatic cancer and squamous cell carcinoma cell lines. But, this has not been shown in ovarian cancer. To investigate the potential association between loss of sensitivity to TGF-β and expression status of transforming growth factor receptor II (TβPRII) Smad4, CDC25A and C-myc in fourteen cell lines derived from ovarian cancer, the expression levels of these genes were examined by semi-quantitative RT-PCR. Normal ovarian Surface tissues were used as controls. Expression of TβRII was detectable in all of fourteen cell lines. Expression of Smad4 was decreased in ten cell lines and nine cell lines overexpressed CDC25A, compared to normal controls. CDC25A gene was overexpressed in 88% (8/9) of tumorigenic cell lines as determined by xenografts in nude mice, and only in 20% (1/5) of non-tumorigenic cell lines (P < 0.05). C-myc was not overexpressed in any of these cell lines. The loss of sensitivity to TGF-β of cell lines derived from ovarian cancers may be related to (1) a decreased expression of Smad4, which mediates TGF-β induced growth inhibition; and/or (2) an overexpression of CDC25A. This overexpression correlates with increased tumorigenicity of ovarian cancer cell lines. The loss of sensitivity to TGF-β is not associated with a lack of TβRII.