The antiestrogen tamoxifen is one of the most successful drugs in the endocrine treatment of breast cancer and significantly reduces the risk of recurrence and death. Antiestrogens act by inhibiting the production of growth-stimulatory factors as well as by activating peptides with growth-inhibitory effects like transforming growth factor- beta (TGF-beta). In hormone-responsive breast cancer cells treatment with antiestrogens leads to the conversion of TGF-beta1 into a biologically active form. Expression of TGF-beta2 and TGF-beta receptor (TbetaR) II is induced via a transcriptional mechanism involving p38 MAP kinase. Inhibition of p38 abolishes antiestrogen-dependent growth inhibition. However, the role of TGF-beta in breast cancer progression is ambiguous, as it was shown to display both tumor-suppressing and -enhancing effects. A polymorphism in the promoter of TGF-beta2 that enhances expression of the protein was associated with lymph node metastasis in breast cancer patients, pointing to a role of TGF-beta2 in the process of invasion. An immunohistochemical study on TbetaRI and TbetaRII expression in breast cancer tissues indicates that the estrogen receptor (ER) status of a tumor is an important marker and a potential mediator of the transition of TGF-beta from tumor suppressor to tumor promoter. In ER-negative tumors, expression of TbetaRII was associated with a subset of tumors that appeared to be highly aggressive, leading to strongly reduced overall survival times. Further characterization of the influence of ER expression on TGF-beta signal transduction shows that ER-alpha plays a crucial role in TGF-beta signaling.

Purpose: The role of transforming growth factor ␤ (TGF-␤) in breast cancer is ambiguous; it can display both tumor suppressing and enhancing effects. Activation of the TGF-␤ signal transduction system is subject to hormonal regulation. This study was conducted to further analyze the role of TGF-␤ receptors in breast cancer and to evaluate their significance as prognostic markers. Experimental Design: Expression of TGF-␤ receptor I (T␤RI) and TGF␤ receptor II (T␤RII) was retrospectively analyzed by immunohistochemistry in 246 breast cancer patients.Results: Expression of T␤RI was strongly correlated with tumor size (P < 0.001) and nodal status (P ‫؍‬ 0.012) but only weakly with overall survival (P ‫؍‬ 0.056). In contrast, T␤RII was prognostic for overall survival in univariate analysis (P ‫؍‬ 0.0370). In estrogen receptor (ER) -negative patients T␤RII expression was correlated with highly reduced overall survival (P ‫؍‬ 0.0083). In multivariate analysis T␤RII proved to be an independent and highly significant prognostic marker with a hazard ratio of 6.8. Simultaneous loss of both ER and T␤RII was associated with longer overall survival times comparable with those of ER-positive patients.Conclusions: The results of this exploratory study show that T␤RII is an independent, highly significant prognostic indicator for overall survival in ER-negative patients. In addition our results are supportive of a mechanism of breast cancer progression in which a selective loss of the tumor inhibitory action of TGF␤ takes place, whereas tumorpromoting aspects remain intact.

The excessive matrix deposition in lung fibrosis is thought to be due to enhanced formation and activity of TGFβ1, which stimulates synthesis and inhibits degradation of matrix proteins. The cellular mechanisms triggered by TGFβ1 are still incompletely understood. Recently, a novel transcriptional target of TGFβ1 has been identified, i.e. the human serum and glucocorticoid dependent kinase hSGK1. The present study has been performed to explore whether TGFβ1 stimulates hSGK1 transcription in lung fibroblasts and whether lung fibrosis is associated with enhanced hSGK1 expression. As evident from Northern Blotting, TGFβ1 strongly upregulates hSGK1 in human lung fibroblasts, an effect partially reversed by p38-kinase inhibitor SB203580. In situ hybridization experiments reveal that in intact lung tissue hSGK1 is expressed in single type II alveolar pneumocytes and macrophages. In contrast, in fibrotic lung tissue a dramatic upregulation of hSGK1 mRNA as well as a strong expression of hSGK1 protein is observed in epithelial cells and interstitial cells comprising macrophages and fibroblasts. In conclusion, in lung fibrosis, the serine/threonine kinase hSGK1 is upregulated, an effect at least partially accounted for by TGFβ1. The full effect of TGFβ1 requires the activation of p38 kinase.