Transforming Growth Factor β1: Implications in Adrenocortical Tumorigenesis

TGF beta1, a multifunctional growth modulator, inhibits the proliferation of epithelial eels. TGF beta1 signaling is dependent on the heterodimerization of the TGF beta1 receptor II (TGF beta 1RII) with the TGF beta1 receptor I (TGF beta 1RI). The cytoplasmic proteins Smads are the mediators of the TGF beta1 signal. TGF beta1 regulates adult and fetal adrenal growth and function. Previously we have shown by Northern analysis that TGF beta 1mRNA was well expressed in normal adrenal and in adrenocortical adenomas but reduced in carcinomas. To investigate whether TGF beta1 receptors may act as tumor suppressors of adrenal tumorigenesis, 16 adenomas and 12 carcinomas were studied. We have used SSCP analysis to scan for inactivating mutations in carcinomas. All tumor samples were negative for somatic alterations of both genes. A competitive RT-PCR system was developed to compare the levels of expression of TGF beta1, TGF beta 1R-I and TGF beta 1R-II, Smad-2 and Smad-4 genes in all tumors. In our study, we confirmed the presence of reduced levels of TGF beta1 in carcinomas. On the contrary, Smad-4 gene levels were elevated in carcinomas when compared to that of adenomas. No significant differences were observed in gene expression of TGF beta 1RI and Smad-2. Our results suggest that mutations of TGF beta1 receptors appear not to be involved in adrenal tumorigenesis. Adrenal carcinomas showed a significant reduction of the TGF beta1 mRNA levels but on the contrary Smad 4 mRNA levels were significantly increased.