Role of TGF-β signaling in uterine carcinosarcoma

Uterine carcinosarcomas (UCS) are rare (3-4%) but highly aggressive, accounting for a disproportionately high (16.4%) mortality among uterine malignancies. Transforming growth factor beta (TGF beta) is a multifunctional cytokine that regulates important cellular processes including epithelial-mesenchymal transition (EMT). Existence of biphasic elements and a report demonstrating amplification of TGF beta at 19q13.1 prompted us to investigate the role of TGF beta signaling in UCS. Here we demonstrated the components of TGF beta pathway are expressed and functional in UCS. TGF beta-I induced significant Smad2/3 phosphorylation, migration and EMT responses in UCS cell lines which could be attenuated by the TGF beta receptor I (TGF beta R-I) or TGF beta receptor I/II (TGF beta R-I/II) inhibitor developed by Eli Lilly and company. Importantly, TGF beta-I induced proliferation was c-Myc dependent, likely through activation of cell cycle. c-Myc was induced by nuclear translocation of nuclear factor of activated T cells (NFAT-1) in response to TGF beta-I. Inhibition of NFAT-1 or TGF beta R-I blocked c-Myc induction, cell cycle progression and proliferation in UCS. In corroboration, mRNA levels of c-Myc were elevated in recurrent versus the nonrecurrent UCS patient samples. Interestingly, in the absence of exogenous TGF beta the TGF beta R-I/II inhibitor enhanced proliferation likely through non-Smad pathways. Thus, inhibition of TGF beta R-I could be efficacious in treatment of UCS.